Pharmacokinetics — Absorption
Absorption is the process by which a drug moves from its site of administration into the systemic circulation. It is the first critical step in the pharmacokinetic sequence of Absorption, Distribution, Metabolism, and Excretion (ADME), and it fundamentally determines the onset, magnitude, and duration of a drug’s therapeutic effect. A thorough understanding of the mechanisms, factors, and clinical implications of drug absorption is essential for rational prescribing, dosing optimisation, and preventing drug interactions. For the South African Pharmacy Council (SAPC) examination, absorption pharmacology frequently appears in clinical case scenarios, multiple-choice questions, and calculation-based problems. This chapter provides comprehensive coverage of all aspects of drug absorption relevant to pharmacy practice in South Africa.
Definitions and Fundamental Concepts
Before exploring the mechanisms and determinants of absorption, it is essential to establish precise definitions for key pharmacokinetic terms. These definitions form the vocabulary that the SAPC expects candidates to command with accuracy.
Bioavailability (F) is defined as the fraction of an administered drug dose that reaches the systemic circulation unchanged, expressed as a decimal (f) or percentage (%). When a drug is administered intravenously, its bioavailability is by definition 100%, as the drug is delivered directly into the bloodstream. For any other route of administration, bioavailability represents a comparison to this ideal. Absolute bioavailability compares the systemic exposure after an extravascular route to that after an intravenous reference dose, calculated as F = (AUCₒᵥ × Doseᵢᵥ) / (AUCᵢᵥ × Doseₒᵥ). Relative bioavailability compares the systemic exposure of two different formulations or routes of the same drug.
Absorption rate constant (ka) describes the velocity at which a drug moves from its site of administration into the bloodstream. A larger ka indicates faster absorption. The ka is a first-order rate constant with units of inverse time (per hour or per minute), and it is used in pharmacokinetic modelling to describe the rising phase of the plasma concentration-time curve.
Peak plasma concentration (Cmax) is the maximum plasma drug concentration achieved after administration, prior to any redistribution or elimination. The time to reach Cmax is referred to as Tmax. Both parameters are influenced by the absorption rate and the elimination rate, and they have clinical implications for the onset and intensity of drug effect.
Area under the curve (AUC) represents the total systemic exposure to a drug over time, from the time of administration until the drug is completely eliminated from the circulation. The AUC is proportional to the absorbed dose and is used in calculating absolute and relative bioavailability.
How Drugs Cross Biological Membranes
Drug absorption is fundamentally governed by the physical and chemical properties of the drug molecule and the structural characteristics of the biological membranes it must traverse. Understanding membrane physiology is therefore a prerequisite to understanding absorption pharmacology.
Structure of Biological Membranes
Biological membranes are composed primarily of a phospholipid bilayer approximately 7–10 nanometres thick. The hydrophilic phosphate heads of the phospholip molecules face outward into the aqueous environments on either side of the membrane (the extracellular fluid and the cytoplasm), while the hydrophobic fatty acid tails face inward, creating a self-sealing barrier that is impermeable to most water-soluble substances. This arrangement is described by the fluid mosaic model, which also incorporates cholesterol molecules embedded within the bilayer (regulating membrane fluidity and permeability) and a variety of membrane proteins that serve structural, enzymatic, receptor, and transport functions.
The key functional consequence of membrane structure is that lipophilic, non-polar molecules cross membranes readily by passive diffusion, while hydrophilic, charged, or large polar molecules cannot and must instead use specialized transport mechanisms or be absorbed through routes that bypass biological membranes (such as intravenous injection directly into the bloodstream).
Mechanisms of Drug Transport Across Membranes
Drugs cross biological membranes through several distinct mechanisms, each with characteristic features, energy requirements, and clinical implications.
Passive diffusion is the most important mechanism for the absorption of most drugs. It operates according to Fick’s law of diffusion, which states that the rate of diffusion is proportional to the concentration gradient across the membrane, the surface area of the membrane, and the partition coefficient of the drug (a measure of its lipid solubility relative to its aqueous solubility), and inversely proportional to the membrane thickness. The key features of passive diffusion are that it requires no energy, proceeds only down a concentration gradient, and involves the drug dissolving in the lipid bilayer. The vast majority of orally administered small-molecule drugs (molecular weight < 500 Da) are absorbed by passive diffusion. Factors that favour passive diffusion include high lipid solubility (high partition coefficient), small molecular size, high concentration gradient between the GI lumen and plasma, and a low degree of ionisation at the site of absorption.
Carrier-mediated transport encompasses both facilitated diffusion and active transport. Facilitated diffusion uses specific membrane transporter proteins to shuttle drugs across the membrane along a concentration gradient, without energy expenditure. Active transport, in contrast, can move drugs against a concentration gradient and requires ATP hydrolysis or coupling to another energy source. Carrier-mediated transport is structurally specific — the transporter protein recognizes particular molecular features, so only certain drugs can be transported by a given carrier. Clinically important examples include the intestinal absorption of levodopa via the L-type amino acid transporter 1 (LAT1), gabapentin via the LAT2 transporter, and the intestinal uptake of bromocriptine and metformin via organic cation transporters (OCTs). Active transport is particularly important at the blood-brain barrier, in hepatocyte uptake, and in renal tubular secretion.
Paracellular absorption refers to the passage of drug molecules through the water-filled pores between adjacent epithelial cells, bypassing the cells themselves. The tight junctions between enterocytes restrict paracellular movement, making this route relatively minor for most drugs. It is most relevant for hydrophilic drugs with low molecular weights (such as metformin, which is partly absorbed paracellularly) and for drugs absorbed from sites where tight junctions are relatively leaky, such as the nasal epithelium or the buccal mucosa. Paracellular absorption bypasses first-pass metabolism.
Transcytosis (vesicular transport) involves the engulfment of a drug by the cell membrane on one side, transport within a vesicle across the cell cytoplasm, and release at the opposite membrane surface. This mechanism is used for large molecules such as peptides, proteins, and nanoparticles, including insulin, enoxaparin, and certain vaccine components. Transcytosis is a minor route for conventional small-molecule drugs but is an active area of research for the oral delivery of biologics.
Ion-pair formation is a special mechanism by which some highly polar drugs (such as sotalol or sulphasalazine) can be absorbed more efficiently than their physicochemical properties would predict. The drug molecule pairs with an endogenous anion or cation to form a neutral, lipophilic complex that can diffuse across the membrane. Once inside the cell or bloodstream, the pair dissociates, releasing the active drug.
Fick’s Law and the Rate of Passive Diffusion
Fick’s first law of diffusion, as applied to drug absorption, can be expressed as:
Rate of absorption = (D × A × Cs − Cp) / h
Where D is the diffusion coefficient of the drug in the membrane, A is the surface area available for absorption, Cs is the concentration at the site of absorption (e.g., GI lumen), Cp is the concentration in plasma (the back-pressure), h is the membrane thickness, and (Cs − Cp) represents the concentration gradient. This equation illustrates several clinically important principles: drugs are absorbed more rapidly when given as solutions rather than solid dosage forms (larger effective surface area and no dissolution step); drugs are absorbed more rapidly when the concentration at the absorption site is high (larger dose, divided doses, or rapid dissolution); and drugs that achieve high plasma concentrations early can experience “absorption flip” — where the back-pressure from plasma concentration slows further absorption.
Physicochemical Determinants of Absorption
Lipophilicity and the Partition Coefficient
The lipophilicity of a drug — its tendency to partition into lipid environments rather than aqueous environments — is the single most important physicochemical determinant of its membrane permeability and, by extension, its absorption. Lipophilicity is measured experimentally as the partition coefficient (P) or distribution coefficient (D), which quantifies the ratio of a drug’s solubility in an organic solvent (typically octanol) to its solubility in water. A high partition coefficient indicates high lipid solubility and, within limits, favourably rapid membrane diffusion.
There is, however, an important nuance: an excessively lipophilic drug may have poor oral bioavailability because it cannot dissolve sufficiently in the aqueous contents of the gastrointestinal tract. An optimum balance of lipophilicity and hydrophilicity is required for oral absorption. This concept is captured by Lipinski’s rule of five, which states that for a drug to be well absorbed orally, it should have: a molecular weight less than 500 Da, a partition coefficient (log P) no greater than 5, no more than 5 hydrogen bond donor groups, and no more than 10 hydrogen bond acceptor groups. These rules are widely used in drug discovery and formulation and are frequently examined in pharmacy assessments.
Ionisation, pKa, and the pH Partition Hypothesis
The degree of ionisation of a drug at a given absorption site profoundly influences its ability to cross membranes by passive diffusion, because only the non-ionised (unionised) form of a drug is sufficiently lipophilic to dissolve in the membrane lipid bilayer. The pH partition hypothesis states that drugs will be absorbed preferentially from gastrointestinal compartments where they exist predominantly in the unionised form.
The relationship between ionisation, pH, and the ionisation constant (pKa) of a drug is governed by the Henderson-Hasselbalch equations:
For weakly acidic drugs: pH = pKa + log([A⁻]/[HA])
For weakly basic drugs: pH = pKa + log([B]/[BH⁺])
These equations reveal that the fraction of drug in the unionised form depends on both the drug’s pKa and the pH of the environment. A weakly acidic drug (e.g., aspirin, pKa ≈ 3.5) will be predominantly unionised in the acidic stomach (pH 1.5–3.5), favouring rapid absorption from the gastric mucosa. A weakly basic drug (e.g., morphine, pKa ≈ 8.0) will be mostly ionised in the stomach and therefore poorly absorbed there; absorption occurs primarily in the small intestine where the pH is approximately 6.0–7.0, at which point a greater fraction of the base is unionised.
| Drug type | Example | pKa | % Unionised in stomach (pH 1.5) | % Unionised in intestine (pH 6.5) | Primary absorption site |
|---|---|---|---|---|---|
| Weakly acidic | Aspirin | 3.5 | ~99% | ~0.1% | Stomach |
| Weakly acidic | Phenobarbital | 7.4 | ~0.1% | ~50% | Stomach and intestine |
| Weakly basic | Morphine | 8.0 | ~0.01% | ~3.1% | Small intestine |
| Weakly basic | Codeine | 8.2 | ~0.005% | ~4.8% | Small intestine |
| Weakly basic | Diphenhydramine | 8.8 | ~0.001% | ~1.6% | Small intestine |
| Strongly acidic | Furosemide | 3.9 | ~99.6% | ~0.3% | Stomach (limited overall due to low solubility) |
| Strongly basic | Amitriptyline | 9.4 | ~0% | ~0.08% | Small intestine (but absorption is variable) |
Important caveats regarding the pH partition hypothesis:
The pH partition hypothesis is a useful framework but is an oversimplification in several respects. Many drugs have multiple ionisable groups, complicating the simple monoacidic or monobasic models. Some drugs have pKa values at which they exist in a zwitterionic (both positively and negatively charged) form, which reduces membrane permeability disproportionately. Additionally, active transport mechanisms and specialised uptake transporters can override passive absorption predictions — for example, furosemide, despite being a weakly acidic drug with high theoretical gastric absorption, is actually poorly absorbed from the stomach because it is actively secreted by anion transporters in the proximal tubule and has low passive permeability; its absorption is variable and primarily from the small intestine, where active uptake transporters (OAT1, OAT3) and passive diffusion both contribute. Finally, drugs with very low solubility (such as furosemide, digoxin, and itraconazole) can have absorption that is limited more by dissolution rate than by membrane permeability.
SAPC examination note: Questions on pH partition often require you to predict the direction of passive absorption or to explain why a drug is better absorbed in one GI compartment than another. Be prepared to apply Henderson-Hasselbalch calculations and to explain exceptions to the general rule. In South African practice, remember that concurrent use of antacids or acid-suppressing agents can alter gastric pH sufficiently to change the absorption profile of pH-dependent drugs.
Gastrointestinal Absorption: The Oral Route
The oral route is the most commonly used and most extensively studied route of drug administration. It is preferred in most clinical settings because of its convenience, cost-effectiveness, and generally acceptable safety profile compared to invasive routes. However, the oral route also presents the greatest number of barriers and variables that can affect drug absorption.
Anatomical and Physiological Considerations
Drugs administered orally must navigate a succession of anatomically and physiologically distinct environments, each of which can affect the drug’s stability, solubility, and rate of absorption.
The oral cavity offers a relatively limited absorptive surface, but it is the site of absorption for sublingual (under the tongue) and buccal (between cheek and gum) dosage forms. The oral mucosa is thin (approximately 100–600 μm) and well-vascularised, allowing drugs to bypass first-pass metabolism if absorbed directly into the systemic circulation via the internal jugular and brachiocephalic veins. Drugs absorbed via the sublingual or buccal route (e.g., glyceryl trinitrate for angina, buprenorphine for pain, midazolam for seizures) must be sufficiently lipophilic and stable in the aqueous environment of saliva.
The stomach presents several barriers to drug absorption. Its highly acidic environment (pH 1.5–3.5) can cause acid-catalysed degradation of drugs that are unstable at low pH (such as penicillin G, erythromycin, and omeprazole, which is enteric-coated specifically to bypass the stomach). The gastric mucosa is covered by a mucus-bicarbonate barrier that limits direct contact between drugs and the absorptive enterocyte surface. The surface area of the gastric mucosa is comparatively small (approximately 1 m²) relative to the small intestine. The gastric emptying rate is a critical determinant of the overall rate of oral absorption, as it determines when the drug reaches the large absorptive surface of the small intestine. Gastric emptying is influenced by the composition of the meal, the physical state of the dosage form, the patient’s posture, and certain medications (prokinetics accelerate it; anticholinergics, opioids, and tricyclic antidepressants delay it).
The small intestine is the principal site of oral drug absorption. It has a vast absorptive surface area of approximately 200 m², generated by the presence of villi and microvilli (the intestinal mucosal folds). The intestinal epithelium consists primarily of absorptive enterocytes (characterised by their brush border membrane, rich in digestive enzymes and transporters), goblet cells (mucus-secreting), Paneth cells (immune function), and M cells (sampling of luminal antigens for gut-associated lymphoid tissue). The small intestinal epithelium is covered by an unstirred water layer that represents an additional barrier to diffusion. Bile salts, secreted in response to fat in the intestinal lumen, are powerful biological surfactants that can solubilise lipophilic drugs and enhance their absorption (as in the case of ciclosporin, where the Sandimmune formulation uses a microemulsion to pre-solubilise the drug). The large intestine and colon absorb water and electrolytes and serve as sites for absorption of drugs formulated as colon-targeted delivery systems or sustained-release formulations. The colon has a relatively lower surface area and fewer digestive enzymes but can be important for the absorption of drugs that are unstable in the upper GI tract or that are specifically designed for colonic delivery (such as budesonide for inflammatory bowel disease or targeted chemotherapy agents).
Dissolution and the Biopharmaceutics Classification System
Before a drug in a solid oral dosage form can be absorbed, it must first dissolve in the gastrointestinal fluids. The rate of dissolution is a critical rate-limiting step for drugs with low aqueous solubility, and it can significantly influence the rate and extent of absorption.
The Biopharmaceutics Classification System (BCS) classifies drugs based on two key parameters: their aqueous solubility and their intestinal permeability. This classification has profound implications for predicting oral absorption, for regulatory decisions about bioequivalence, and for clinical pharmacy practice:
Class I drugs have high solubility and high permeability. They are absorbed readily and completely (F > 85%) by passive diffusion. The rate-limiting step is gastric emptying rather than dissolution or permeability. Examples include metformin, paracetamol, and ibuprofen. For Class I drugs, formulation differences are less clinically significant, and immediate-release oral formulations are generally well-absorbed regardless of whether they are taken with or without food.
Class II drugs have low solubility but high permeability. Their absorption is dissolution-rate limited. Enhancing dissolution through formulation strategies (micronisation, solid dispersions, nanoparticle formulations) is a key goal in drug product development. Examples include ibuprofen (at high doses), amiodarone, and itraconazole. Food can significantly increase the absorption of some Class II drugs (particularly those that are fat-soluble, as dietary fat stimulates bile secretion) and decrease absorption of others (by coating the drug particles or altering gastric pH).
Class III drugs have high solubility but low permeability. Their absorption is permeability-rate limited. They may be absorbed incompletely even if they dissolve rapidly. Strategies to enhance absorption include the use of permeation enhancers (such as sodium caprate, used in some formulations of metformin and insulin) or carrier-mediated transport mechanisms. Examples include metformin, cimetidine, and levofloxacin.
Class IV drugs have both low solubility and low permeability. They present the greatest challenges for oral delivery and often have highly variable and incomplete bioavailability. Examples include amphotericin B, ciclosporin (in older formulations), and saquinavir. These drugs often require specialised formulation technologies (microemulsions, lipid-based delivery systems) to achieve adequate oral absorption.
| BCS Class | Solubility | Permeability | Absorption characteristics | Examples | Clinical implication |
|---|---|---|---|---|---|
| Class I | High | High | Complete; gastric emptying is rate-limiting | Paracetamol, metformin, ibuprofen | Food effects minimal; bioequivalence straightforward |
| Class II | Low | High | Dissolution-rate limited; variable with food | Itraconazole, griseofulvin, amiodarone | Formulation critical; take with food if fatty meal enhances absorption |
| Class III | High | Low | Permeability-rate limited; variable | Metformin, cimetidine, ranitidine | Permeation enhancers may help; avoid drugs that reduce permeability |
| Class IV | Low | Low | Severely limited; highly variable | Amphotericin B, chloroquine (oral) | Often require alternative routes; oral bioavailability unpredictable |
First-Pass Metabolism and Presystemic Metabolism
Definitions and Distinction
Presystemic metabolism (also called the first-pass effect or first-pass metabolism) refers to all the metabolic processes that a drug undergoes before it reaches the systemic circulation, encompassing both gastrointestinal metabolism and hepatic metabolism. The term “first-pass” refers to the fact that after oral administration, the absorbed drug is carried directly to the liver via the portal vein before it enters the systemic circulation. If the liver metabolises a significant fraction of the drug during this first transit, the oral bioavailability will be substantially reduced. Presystemic metabolism is not limited to oral administration — it can also occur after rectal, dermal, pulmonary, and oral transmucosal administration, depending on the anatomical drainage of the absorption site.
Hepatic first-pass metabolism is the component of presystemic metabolism that occurs in the liver. When a drug is swallowed and absorbed from the GI tract, it enters the portal circulation and travels to the liver where it may undergo extensive metabolism before reaching the systemic circulation. The hepatic extraction ratio (E) quantifies the fraction of drug removed by the liver during a single pass: E = (Cin − Cout) / Cin. Drugs with a high extraction ratio (E > 0.7) are classified as high extraction drugs; their hepatic clearance is flow-dependent and is relatively unaffected by changes in enzyme activity but is significantly altered by changes in liver blood flow. Examples include propranolol, morphine, lignocaine, and verapamil. Drugs with a low extraction ratio (E < 0.3) are low extraction drugs; their hepatic clearance is enzyme-activity-dependent and is sensitive to CYP enzyme induction or inhibition but relatively insensitive to hepatic blood flow. Examples include phenytoin, warfarin, and diazepam.
Gastrointestinal Metabolism
The gastrointestinal tract itself is a metabolically active organ that can significantly alter drug bioavailability even before the drug reaches the liver. Several mechanisms contribute to GI metabolism:
Gastric acid hydrolysis is the degradation of drugs by the low pH of the stomach. Penicillin G is a classical example of a drug that is rapidly inactivated by gastric acid, which is why it is formulated as a more acid-stable ester (benzathine penicillin G) for oral use or administered by injection. Erythromycin base is also degraded by gastric acid and is therefore formulated as enteric-coated tablets or as the more acid-stable estolate or ethylsuccinate esters.
Intestinal brush border enzymes include peptidases and glycosidases that can metabolise peptide and glycopeptide drugs. L-DOPA, for example, is decarboxylated to dopamine by aromatic L-amino acid decarboxylase in the intestinal mucosa before it can be absorbed, which is why it is always co-administered with benserazide or carbidopa (peripheral DOPA decarboxylase inhibitors) to prevent this presystemic conversion.
Intestinal cytochrome P450 enzymes, particularly CYP3A4, are expressed in enterocytes at levels that can be clinically significant. CYP3A4 in the intestinal wall can metabolise a wide range of drugs during the absorption process, contributing to low oral bioavailability. Notable substrates include ciclosporin, tacrolimus, midazolam, felodipine, and many others. The intestinal CYP3A4 content varies between individuals and can be induced or inhibited by co-administered drugs, leading to unpredictable bioavailability.
Gut wall efflux transporters, particularly P-glycoprotein (P-gp), expressed on the apical (luminal) surface of enterocytes, actively pump drugs back into the intestinal lumen, reducing their absorption. P-gp and CYP3A4 together constitute a coordinated intestinal barrier system that limits the oral bioavailability of many drugs (the “CYP3A4-P-gp axis”). Rifampicin is both a CYP3A4 inducer and a P-gp inducer, leading to dramatically reduced bioavailability of many co-administered drugs when used concurrently.
Clinical Examples of First-Pass Metabolism
The extent of first-pass metabolism varies greatly between drugs and has important clinical implications for route selection, dosing, and drug interactions.
Propranolol is a classical example of a drug with extensive first-pass metabolism. Its oral bioavailability is approximately 25–30%, compared to 100% when given intravenously. The first-pass metabolism of propranolol occurs both in the liver (where it is extensively metabolised by CYP2D6 and CYP1A2) and in the intestinal wall (CYP3A4). The degree of first-pass metabolism shows interindividual variability due to genetic polymorphisms in CYP2D6 (with poor metabolisers achieving higher plasma concentrations from a given oral dose) and environmental factors such as smoking (which induces CYP1A2 and reduces propranolol’s first-pass metabolism, paradoxically increasing its systemic exposure). Clinically, the SAPC examination may test whether candidates understand that propranolol oral doses must be much higher than IV doses to achieve equivalent systemic beta-blockade, and that the oral-to-IV potency ratio is approximately 4:1.
Morphine has an oral bioavailability of approximately 30–40% due to extensive first-pass metabolism, primarily glucuronidation in the liver to morphine-6-glucuronide (active) and morphine-3-glucuronide (inactive). The oral-to-parenteral potency ratio for morphine is approximately 3:1. In South Africa, oral morphine is available as immediate-release and controlled-release formulations (MST Continus), and the significant first-pass effect is a key consideration in converting between oral and parenteral dosing in palliative care patients.
Lidocaine is virtually completely metabolised by the liver on first pass, giving it an oral bioavailability of approximately 3–5%. For this reason, lidocaine cannot be given orally for systemic effect and must be administered intravenously for cardiac arrhythmias or intrathecally/epidurally for anaesthesia.
Nitrates (glyceryl trinitrate, isosorbide dinitrate) undergo extensive first-pass metabolism in the liver, which is why sublingual, transdermal, and intravenous routes are used for systemic effects, while oral formulations require much higher doses to compensate for the first-pass effect.
Testosterone is subject to extensive first-pass hepatic metabolism, which led to the development of transdermal testosterone patches and gels as alternatives to oral testosterone for hormone replacement therapy.
南非（South Africa）Specific Considerations: Traditional medicines and herbal remedies used in South African primary healthcare can significantly induce or inhibit both intestinal and hepatic CYP enzymes, altering first-pass metabolism of conventional medicines. St John’s wort (sometimes used for depression in complementary medicine) is a potent inducer of CYP3A4, P-gp, and several other CYP enzymes, and can dramatically reduce the bioavailability and efficacy of medicines including ciclosporin, tacrolimus, warfarin, oral contraceptives, and antiretroviral drugs. Garlic supplements and ginkgo biloba also have CYP-inducing properties. Patients in South Africa who use traditional or complementary medicines should be asked about this explicitly, as these interactions are particularly important for drugs with narrow therapeutic indices.
Membrane Transporters in Drug Absorption
Transporter proteins expressed in the gastrointestinal epithelium, hepatocytes, renal tubules, and the blood-brain barrier play critical roles in determining the rate and extent of drug absorption, distribution, and elimination. Understanding transporter pharmacology is increasingly important for the SAPC examination, as drug-transporter interactions are a common basis for drug interactions and interindividual variability in drug response.
ATP-Binding Cassette (ABC) Transporters
ABC transporters use ATP hydrolysis to actively pump substrates across cell membranes, against concentration gradients. They are primary active transporters.
P-glycoprotein (P-gp, MDR1, ABCB1) is the most clinically important ABC transporter in absorption pharmacology. It is expressed at high levels on the apical (luminal) surface of enterocytes, on the canalicular membrane of hepatocytes, on the brush border of renal proximal tubules, and on the endothelial cells of the blood-brain barrier. Its physiological function appears to be protective — it acts as a defence mechanism, pumping potentially toxic xenobiotics back into the intestinal lumen, into bile, and into urine, and restricting their entry into the brain.
Clinically important P-gp substrates include: digoxin (a classic P-gp substrate where monitoring is essential), ciclosporin, tacrolimus, quinidine, loperamide, morphine (to some extent), colchicine, dabigatran etexilate, and many chemotherapeutic agents (doxorubicin, vincristine, paclitaxel). Inhibitors of P-gp (such as ketoconazole, erythromycin, clarithromycin, verapamil, diltiazem, amiodarone, and quinidine) can increase the bioavailability and systemic exposure of P-gp substrates, potentially causing toxicity. Conversely, inducers of P-gp (such as rifampicin, phenytoin, carbamazepine, and St John’s wort) can reduce the bioavailability and efficacy of P-gp substrates.
In South Africa, the interaction between rifampicin (a potent P-gp and CYP3A4 inducer) and ciclosporin or tacrolimus in transplant patients is a particularly important clinical concern. Rifampicin co-administration can reduce ciclosporin blood concentrations by 60–80%, necessitating significant dose increases and close therapeutic drug monitoring.
Breast Cancer Resistance Protein (BCRP, ABCG2) is expressed on the intestinal epithelium, liver canaliculi, renal tubules, and the blood-brain barrier. It has overlapping substrate specificity with P-gp and is involved in the transport of drugs such as methotrexate, sulfasalazine, rosuvastatin, topotecan, and several tyrosine kinase inhibitors (sunitinib, sorafenib). Gemfibrozil is a BCRP inhibitor and can increase the exposure to BCRP substrates.
Multidrug Resistance-Associated Proteins (MRPs, ABCCs) are a family of transporters involved in the export of organic anions and glucuronide, sulphate, and glutathione conjugates. They are important in biliary excretion and in limiting the intestinal absorption of anionic drugs and drug metabolites.
Solute Carrier (SLC) Transporters
SLC transporters facilitate the movement of drugs across membranes down concentration gradients or in exchange for ions, without direct ATP hydrolysis. They include several families of clinical importance in absorption pharmacology.
Organic Anion Transporting Polypeptides (OATPs, SLCO family) are expressed on the sinusoidal membrane of hepatocytes (where they mediate hepatic uptake), on the apical membrane of enterocytes (intestinal absorption), and on the blood-brain barrier. OATPs transport a wide range of anionic drugs and some neutral compounds. Clinically important OATP substrates include: bosentan, atrasentan, valsartan, olmesartan, fluvastatin, rosuvastatin, atorvastatin, lenvatinib, and methotrexate. Rifampicin is a potent inhibitor of OATP1B1 and OATP1B3, and this inhibition underlies the clinically important interaction between rifampicin and bosentan (where rifampicin can reduce bosentan exposure by 50–90%) and between rifampicin and rosuvastatin (where co-administration can increase rosuvastatin exposure due to OATP inhibition, though rifampicin also induces hepatic metabolism, creating complex net effects). In South Africa, patients on bosentan for pulmonary arterial hypertension require careful monitoring when rifampicin is introduced or withdrawn.
Organic Anion Transporters (OATs, SLC22A family) are expressed in the kidney (basolateral membrane of proximal tubules), liver, and brain. They mediate the renal tubular secretion of anionic drugs including penicillins, cephalosporins,loop diuretics, thiazide diuretics, NSAIDs, methotrexate, and zidovudine. Probenecid inhibits OATs and is used therapeutically to reduce the renal clearance of certain drugs (for example, reducing the renal clearance of cefoxitin or increasing the plasma concentrations of zidovudine, though the latter use is limited by practical considerations).
Organic Cation Transporters (OCTs, SLC22A family) mediate the uptake of organic cations across basolateral membranes in the kidney, liver, and intestine. OCT1 (SLC22A1) and OCT2 (SLC22A2) are relevant to hepatic and renal uptake respectively. Important OCT substrates include metformin, cisplatin, atenolol, imatinib, and morphine (to some extent). Genetic polymorphisms in OCT1 (found in approximately 5–10% of individuals of European descent, and also occurring in South African populations) can reduce the hepatic uptake and efficacy of metformin and imatinib.
Peptide Transporters (PEPT1, PEPT2, SLC15A family) are proton-coupled symporters expressed in the intestinal epithelium (PEPT1), renal tubules (PEPT2), and other tissues. They transport dipeptides and tripeptides and are exploited for the oral delivery of peptide-like drugs including beta-lactam antibiotics (ampicillin, cephalexin), ACE inhibitors (benazepril, enalapril), the antiviral valaciclovir (which is a valine ester of aciclovir, transported by PEPT1 to enhance intestinal absorption of aciclovir by approximately 3- to 4-fold over passive diffusion of aciclovir alone), and the antineoplastic agent bestatin.
| Transporter | Location | Direction | Representative substrates | Clinical significance |
|---|---|---|---|---|
| P-gp (MDR1/ABCB1) | Intestine (apical), liver, kidney (apical), BBB | Luminal efflux | Digoxin, ciclosporin, tacrolimus, loperamide, colchicine | Limits oral absorption of many drugs; drug interactions common |
| BCRP (ABCG2) | Intestine (apical), liver, kidney, BBB | Luminal efflux | Methotrexate, rosuvastatin, sulfasalazine, topotecan | Limits oral bioavailability; affects statin efficacy |
| OATP1B1/1B3 (SLCO1B1/1B3) | Liver (sinusoidal), intestine (apical) | Hepatic uptake | Rosuvastatin, atorvastatin, valsartan, bosentan, methotrexate | Rifampicin inhibits; genetic polymorphisms affect statin safety |
| OAT1/3 (SLC22A6/8) | Kidney (basolateral) | Tubular secretion | Penicillins, cephalosporins, methotrexate, NSAIDs | Probenecid inhibits; drug interactions reduce renal clearance |
| PEPT1 (SLC15A1) | Intestine (apical) | Absorption | Beta-lactams, ACE inhibitors, valaciclovir | Pro-drug absorption (valaciclovir has 3-4× higher oral bioavailability than aciclovir) |
| OCT1 (SLC22A1) | Liver (sinusoidal) | Hepatic uptake | Metformin, imatinib, morphine | Genetic polymorphisms affect drug response |
Enterocyte Metabolism and the Intestinal Barrier
The enterocyte is not merely a passive conduit for drug absorption — it is a metabolically active cell that expresses a full complement of drug-metabolising enzymes and transporters that collectively constitute the intestinal barrier. The interplay between absorptive flux (what enters the enterocyte from the lumen), metabolic conversion (what the enterocyte does to the drug), and efflux back into the lumen (what the enterocyte pumps back out) determines the net bioavailability of orally administered drugs.
Intestinal Metabolism
Enterocytes express most of the major Phase I and Phase II drug-metabolising enzymes that are also found in the liver, though generally at lower levels. The most clinically significant intestinal enzyme is CYP3A4, which is expressed at measurable levels in the small intestinal mucosa and can metabolise a wide range of drugs during the absorptive transit. The contribution of intestinal CYP3A4 to the presystemic metabolism of drugs such as ciclosporin, midazolam, felodipine, and saquinavir can be substantial, sometimes exceeding hepatic first-pass metabolism for drugs with high intestinal permeability.
Phase II enzymes expressed in the intestine include UDP-glucuronosyltransferases (UGT1A1, UGT1A3, UGT2B7), sulfotransferases, N-acetyltransferases, and glutathione S-transferases. The activity of these enzymes in the intestine can contribute to the metabolic inactivation of drugs and to the formation of active metabolites. For example, intestinal UGT1A1 metabolises SN-38, the active metabolite of irinotecan, contributing to the drug’s complex pharmacokinetics and limiting the bioavailability of orally administered irinotecan.
The Fence Function of the Enterocyte
The coordinated action of efflux transporters and metabolising enzymes in the enterocyte constitutes a functional barrier that limits the net absorption of many drugs. This concept is illustrated by the case of ciclosporin A. After oral administration, ciclosporin must cross the intestinal epithelium to reach the systemic circulation. P-gp on the apical membrane pumps ciclosporin back into the lumen; CYP3A4 in the enterocyte metabolises it; and the combination of these two barrier mechanisms reduces the oral bioavailability of the unmodified drug from a theoretical maximum of approximately 100% to a clinical reality of about 20–30% in the absence of formulation enhancement. The introduction of the microemulsion formulation (Neoral) improved the oral bioavailability of ciclosporin to approximately 40–50% by pre-solubilising the drug and reducing the dependence on bile for dissolution, but the intestinal barrier mechanisms remained operative. This example is clinically significant in South Africa, where ciclosporin is used in renal transplantation and where therapeutic drug monitoring is mandatory to ensure adequate immunosuppression.
Food Effects on Absorption
Food intake has complex and drug-specific effects on oral drug absorption, mediated through multiple mechanisms including changes in gastric pH, gastric emptying rate, intestinal transit time, bile secretion, splanchnic blood flow, and direct interactions with drug formulation components.
Fatty meals are particularly important for the absorption of lipophilic drugs, as fat stimulates the release of bile salts from the gallbladder, which emulsify dietary fat and simultaneously solubilise lipophilic drugs in mixed micelles, dramatically enhancing their dissolution and absorption. The oral bioavailability of griseofulvin, a classic lipophilic antifungal, is increased significantly when taken with a fatty meal (the approved dosing recommendation is to take it with a fatty meal or milk). Similarly, the absorption of halofantrine, mefloquine, and the liquid softgel capsule formulation of isotretinoin is substantially increased by fatty food. In South Africa, where malaria prophylaxis and treatment drugs are frequently prescribed, candidates should be aware that halofantrine should be taken with fatty food to achieve adequate plasma concentrations.
Grapefruit juice is a potent and clinically important inhibitor of intestinal CYP3A4 and to a lesser extent P-gp and OATP1B1. The furanocoumarins in grapefruit juice (notably bergamottin and 6’,7’-dihydroxybergamottin) cause mechanism-based (irreversible) inhibition of CYP3A4 in the intestinal mucosa, leading to a substantial reduction in the presystemic metabolism of CYP3A4 substrates. Affected drugs include felodipine, nifedipine, amiodipine, simvastatin, lovastatin, atorvastatin, ciclosporin, tacrolimus, midazolam, triazolam, carbamazepine (to a lesser extent), saquinavir, and many others. The effect of grapefruit juice on felodipine can increase its bioavailability by 300–500%, producing significantly enhanced hypotensive effects. The clinical recommendation is to avoid grapefruit juice when taking drugs whose safety and efficacy are critically dependent on predictable CYP3A4 metabolism. This is particularly important for transplant patients on calcineurin inhibitors and for patients on certain statins.
Calcium-rich foods (such as milk, cheese, and calcium-fortified products) can form insoluble chelates with tetracycline antibiotics, fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin), and biphosphonates (alendronate, risedronate), significantly reducing their absorption. Patients should be advised to avoid taking these medicines with dairy products.
Route-Specific Absorption
Intravenous Administration
Intravenous (IV) administration delivers drugs directly into the systemic circulation, bypassing all absorption barriers. The bioavailability of intravenously administered drugs is, by definition, 100%. There is no first-pass metabolism, no dissolution requirement, no gastric emptying delay, and no intestinal permeability limitation. The onset of effect is immediate (limited only by the rate of injection and distribution into the central compartment), and the dose-response relationship is direct and predictable. For these reasons, IV administration provides the greatest control over drug exposure and is the route used when rapid, precise, or high-intensity effect is required, or when the oral route is unavailable or unreliable.
However, IV administration is not without disadvantages. It requires venous access, which may be difficult in some patients; it carries the risk of phlebitis, infection, and embolism; it eliminates the protective function of the GI tract and first-pass metabolism, potentially exposing patients to higher systemic concentrations of active metabolites that are normally generated in small amounts during oral absorption; and it does not allow for self-administration in most outpatient settings. Additionally, drugs that are vesicants or irritants (such as doxorubicin, vancomycin, or diazepam) can cause severe tissue damage if extravasation occurs.
For the SAPC examination, candidates must understand that the IV route is used as the reference standard for bioavailability calculations and that any alternative route’s bioavailability is expressed relative to IV.
Intramuscular Administration
Intramuscular (IM) injection delivers drug into the fluid space within skeletal muscle tissue, from where it is absorbed into the systemic circulation via the muscle capillary network. The absorption rate from IM sites depends on the blood flow to the muscle, the formulation of the drug (aqueous solutions are absorbed more rapidly than oily suspensions or depot formulations), the volume injected, and the site of injection (deltoid muscle has faster absorption than gluteal muscle due to differential blood supply).
The bioavailability of drugs after IM administration is generally high (often 80–100%), and the onset of effect is faster than with oral administration but slower than with IV. IM administration avoids the acidic gastric environment, first-pass metabolism, and dissolution limitations of oral dosage forms. It is suitable for drugs that are poorly absorbed orally, for drugs that are too large or unstable for oral delivery, and for situations where rapid and reliable absorption is required but IV access is not practical.
Examples of IM-administered drugs relevant to South African practice include: benzathine penicillin G (long-acting penicillin for syphilis, rheumatic fever prophylaxis), pethidine (for acute pain, though its active metabolite normeperidine accumulates with repeated dosing), haloperidol (for acute psychosis or agitation), medroxyprogesterone acetate (contraceptive injection, Depo-Provera), ** adrenaline/epinephrine** (for anaphylaxis and cardiac arrest), ceftriaxone (for gonorrhoea, meningitis, and severe infections where outpatient IV therapy is needed), ergometrine/oxytocin (for postpartum haemorrhage management), and vaccines (most vaccines are administered IM, including those in the South African EPI schedule such as the pentavalent vaccine, measles vaccine, and COVID-19 vaccines).
SAHPRA and SAPC note: The choice between IM and IV administration for certain drugs in South Africa often reflects the clinical setting and resource availability. In primary healthcare clinics where IV access may be difficult to obtain, IM administration of drugs such as adrenaline (for anaphylaxis), antibiotics (ceftriaxone), and oxytocics (ergometrine) may be preferred. Candidates should know the appropriate IM dose of drugs that are given both IM and IV, as the doses are not always interchangeable (for example, adrenaline IM for anaphylaxis is given at 0.3–0.5 mg of the 1:1000 solution, whereas IV adrenaline for cardiac arrest is given at much smaller doses of 1 mg of the 1:10000 solution).
Subcutaneous Administration
Subcutaneous (SC) administration involves injection into the loose connective tissue beneath the dermis, between the skin and the underlying muscle. Absorption from SC sites is generally slower than from IM sites, because subcutaneous adipose tissue has a lower blood supply than muscle tissue. However, SC absorption is more predictable and sustained than oral absorption, and SC injections are often less painful than IM injections (making them suitable for chronic self-administration, as in insulin therapy or growth hormone therapy).
The SC route is particularly important for biopharmaceuticals (recombinant proteins, peptides, monoclonal antibodies) that would be degraded in the GI tract and cannot be given orally. Examples include insulin (both human insulin and insulin analogues such as insulin lispro, aspart, and glargine), growth hormone (somatropin), enoxaparin (low molecular weight heparin), erythropoietin (EPO), and granulocyte colony-stimulating factor (G-CSF, filgrastim). Many monoclonal antibodies (trastuzumab, rituximab, bevacizumab) are also administered SC (in formulations such as trastuzumab SC or rituximab SC) in preference to IV infusion, as the SC formulations offer comparable efficacy with shorter administration times and the possibility of home administration.
In South Africa, SC administration is also used for adrenaline in some pre-hospital emergency settings (auto-injectors such as the Epipen for anaphylaxis), for insulin in diabetes management, and for enoxaparin in the prophylaxis and treatment of venous thromboembolism. The bioavailability of enoxaparin after SC administration approaches 90–100%, compared to the very low and unpredictable bioavailability after oral administration (which is essentially zero for unfractionated heparin and low molecular weight heparins, because their large molecular sizes prevent membrane permeation).
Absorption modifiers for SC administration: The rate of SC absorption can be modified by co-administering vasoconstrictors (to slow absorption and prolong effect, as in the case of lignocaine with adrenaline for local anaesthesia) or by formulating drugs in depot matrices (as in the case of leuprolide acetate microspheres or naltrexone depot injections).
Transdermal Administration
Transdermal drug delivery involves the application of drug to the skin surface, from where the drug penetrates the stratum corneum (the outermost layer of the epidermis, which is the principal barrier to percutaneous absorption) and reaches the dermal capillary network for systemic absorption. The transdermal route exploits the fact that the stratum corneum, while it is the main barrier to water loss from the body, is permeable to certain lipophilic, low-molecular-weight drugs. The rate and extent of transdermal absorption are determined by the drug’s physicochemical properties (lipophilicity, molecular weight, ionisation), the condition of the skin (integrity, hydration, temperature), and the formulation and delivery system used.
Transdermal delivery offers several important advantages: it bypasses first-pass metabolism entirely (the drug absorbed through the skin enters the systemic circulation directly via the peripheral venous system, without portal drainage); it provides sustained, controlled release over extended periods (hours to days); it improves patient compliance (once-daily or weekly patches are easier than multiple daily doses); and it allows rapid withdrawal of drug exposure by simply removing the patch. However, it is limited to drugs that are sufficiently lipophilic and potent (requiring daily doses in the low milligram range) and cannot be used for drugs that are hydrophilic, ionised, or require rapid onset of effect.
Clinically important transdermal drugs relevant to South African pharmacy practice include:
Fentanyl patches are used for the management of severe chronic cancer pain and non-cancer pain in opioid-tolerant patients. Fentanyl is approximately 80–100 times more potent than morphine and is highly lipophilic, making it suitable for transdermal delivery. The patches deliver fentanyl at rates of 12.5, 25, 50, 75, and 100 micrograms per hour, providing around-the-clock analgesia for 72 hours. The South African Medicines Control Council (now SAHPRA) has specific regulations governing the prescribing and dispensing of fentanyl patches due to their high abuse potential and the risk of fatal respiratory depression. Pharmacists must ensure that transdermal fentanyl is initiated only in opioid-tolerant patients and that patients are counselled on proper patch use, disposal (used patches still contain significant fentanyl and must be folded and flushed or disposed of safely to prevent accidental paediatric exposure), and the avoidance of heat sources (which can accelerate fentanyl release and cause overdose).
Oestrogen and combined hormone replacement therapy (HRT) patches deliver estradiol or combined estradiol/progestogen across the skin for the management of menopausal symptoms and osteoporosis prevention. Transdermal estradiol avoids the hepatic first-pass metabolism of oral estradiol, resulting in more physiological estradiol-to-estrone ratios and avoiding the stimulation of clotting factor synthesis that occurs with oral oestrogen therapy. In South Africa, transdermal estradiol patches (such as Dermestril, Climara, and Menorest) are available and are considered preferable to oral oestrogen in women at risk for venous thromboembolism or with hepatic dysfunction.
Nicotine patches are used as nicotine replacement therapy (NRT) for smoking cessation. They deliver nicotine transdermally over 16 or 24 hours, reducing the severity of nicotine withdrawal symptoms and helping smokers quit. In South Africa, nicotine patches (Nicorette patch, NicoPatch) are available as unscheduled pharmacy-only medicines, making them accessible without a prescription.
Contraceptive patches (e.g., Evra) deliver ethinyl estradiol and norelgestromin transdermally for hormonal contraception. They are applied weekly (three weeks on, one week off) and offer an alternative to oral contraceptives for women who have difficulty with daily tablet compliance.
Glyceryl trinitrate (GTN) patches are used for the prophylaxis of angina pectoris. They deliver GTN continuously, preventing the nitrate tolerance that develops with frequent dosing of short-acting nitrate formulations (such as sublingual GTN tablets or sprays). The patch is applied in the morning and removed at night, allowing a nitrate-free interval to restore vascular responsiveness.
In South Africa, methylphenidate patches (Daytrana) are not widely available, but clonidine patches (for hypertension and ADHD) and selegiline transdermal patches (for Parkinson’s disease) are used in specialist practice.
SAPC examination note: Candidates should be aware that the rate of transdermal absorption is increased by heat (saunas, hot baths, direct sunlight on the patch area), by occlusion (which increases skin hydration and permeability), and by simultaneous application of occlusive emollients or oils. The rate is decreased by cold, by skin thickening, and by application to areas with thick stratum corneum (palms and soles are less permeable than the upper arm or chest).
Rectal Administration
Rectal administration involves the insertion of a drug into the rectum, where it can be absorbed through the rectal mucosa. The rectal route is clinically useful when oral administration is impractical (vomiting, dysphagia, seizures), when the patient is unconscious, or when a drug’s oral bioavailability is severely limited by first-pass metabolism and an alternative route is not available.
Anatomically, the rectum is divided into two regions with different venous drainage: the upper two-thirds of the rectum drains via the superior rectal vein into the portal vein, carrying absorbed drug to the liver (portal drainage → first-pass metabolism). The lower one-third drains via the middle and inferior rectal veins into the systemic venous circulation (bypassing the portal system and first-pass metabolism). When a rectal suppository is inserted correctly (with the apex of the suppository pointing toward the patient’s head, targeting the upper rectal region), approximately 50% of the absorbed drug may bypass the liver through the inferior and middle rectal veins, partially avoiding first-pass metabolism. However, the distribution of venous drainage is individual and unpredictable, and the actual fraction of drug that avoids first-pass metabolism after rectal administration is variable.
Examples of rectally administered drugs used in South Africa:
Paracetamol suppositories are widely used in South African hospitals and clinics for febrile children and for patients who cannot take oral medication (post-operative nausea and vomiting, patients with vomiting, or those nil per os). Paracetamol suppositories are available in 125 mg and 250 mg doses for children, and the bioavailability of paracetamol from suppositories is generally good (approximately 80–90% relative to oral, though this varies with the formulation and the placement of the suppository).
Anti-emetics such as prochlorperazine (Stemetil) suppositories are used for nausea and vomiting when oral intake is not possible.
Analgesics such as diclofenac suppositories provide effective pain relief, particularly post-operatively or in palliative care.
Laxatives such as bisacodyl and glycerol (glycerin) suppositories are used for constipation.
Diazepam rectal solution (Stesolid) is used for the acute management of status epilepticus in community settings where IV access is not immediately available. The rectal absorption of diazepam is reasonably rapid, providing seizure control within 5–10 minutes.
Promethazine suppositories are used for sedation and emesis in paediatrics.
The rectal route has several limitations: it is inconvenient and not socially acceptable for many patients; absorption can be irregular and incomplete due to variable rectal residency time (defecation may expel the dose before full absorption); some drugs can cause rectal irritation or mucosal damage; and the bioavailability of drugs that are absorbed primarily from the colon (which is distal to the rectum and is reached only if the drug migrates from the rectum) is generally lower than from the oral route.
Pulmonary Administration
Pulmonary drug delivery involves the inhalation of drugs into the respiratory tract, where they can act locally (on the airways and lungs) or be absorbed systemically through the extensive alveolar capillary network. The pulmonary route is unique in that it offers both local and systemic delivery from the same anatomical site, with systemic absorption occurring through the alveolar epithelium directly into the pulmonary venous circulation, which drains to the left heart and the systemic circulation — bypassing both hepatic first-pass metabolism and gastrointestinal absorption barriers. This makes the pulmonary route potentially attractive for drugs that have poor oral bioavailability due to first-pass metabolism, provided they can be formulated for inhalation and are stable in the lung environment.
The respiratory tract is divided into the upper airways (nasopharynx, oropharynx, larynx), the tracheobronchial tree (bronchi, bronchioles), and the alveoli (approximately 300–500 million alveoli with a combined surface area of approximately 70–100 m² and an extremely thin epithelial barrier of 0.1–0.5 μm). The fraction of an inhaled dose that reaches the alveoli (the pulmonary deposition fraction) is determined by the particle or droplet size of the inhaled formulation, the patient’s inhalation technique, and the geometry of the airways.
Particle size and the “ideal” aerodynamic diameter: For drugs intended to act locally in the airways (asthma, COPD), particles with an aerodynamic diameter of 1–5 μm are optimal for deposition in the lower airways and alveoli. Particles larger than 5 μm tend to deposit in the oropharynx and are swallowed (losing the pulmonary advantage). Particles smaller than 0.5 μm may remain in the airstream and be exhaled without depositing. For systemic delivery via the alveoli, particles in the 1–3 μm range are optimal for alveolar deposition.
Devices for pulmonary delivery: Pressurised metered-dose inhalers (pMDIs) are the most widely used inhaler device globally. They contain a drug in suspension or solution in a propellant (historically chlorofluorocarbons, now hydrofluoroalkanes such as HFA-134a and HFA-227) under pressure. The propellant drives the drug out of the actuator as a fast-moving aerosol cloud. pMDIs are widely used in South Africa for the delivery of short-acting beta-agonists (salbutamol, terbutaline), inhaled corticosteroids (fluticasone, budesonide, beclomethasone), long-acting beta-agonists (salmeterol, formoterol), and combination inhalers (fluticasone/salmeterol, budesonide/formoterol). The incorrect use of pMDIs (failure to coordinate actuation with inhalation, too-rapid inhalation, failure to hold breath after inhalation) is a major cause of therapeutic failure, and the SAPC examination frequently tests candidates’ ability to counsel patients on proper inhaler technique.
Dry powder inhalers (DPIs) deliver drugs as a dry powder aerosol generated by the patient’s inspiratory effort. They are breath-actuated (eliminating the need for hand-mouth coordination) and are propellant-free. Examples include the Turbohaler (budesonide, formoterol), Accuhaler/Diskus (fluticasone/salmeterol, salmeterol, fluticasone), and Ellipta (fluticasone/vilanterol, umeclidinium/vilanterol). In South Africa, DPI devices are widely used in the public sector (the national essential medicines list includes inhaled corticosteroids and bronchodilators in DPI form for cost-effectiveness and ease of use) and in the private sector.
Nebulisers generate a fine mist of drug particles suspended in air, suitable for patients who cannot use handheld inhalers (such as young children, the elderly, or patients in acute distress). Nebulised formulations include salbutamol nebuliser solution, ipratropium bromide nebuliser solution, budesonide nebuliser suspension (Pulmicort respules), and tobramycin nebuliser solution (for Pseudomonas aeruginosa colonisation in cystic fibrosis).
Examples of pulmonary-administered drugs relevant to South Africa:
Salbutamol (short-acting beta-agonist, Ventolin, Asthavent) is the most widely used inhaled drug in South Africa for acute asthma and COPD. It provides rapid bronchodilation within minutes. The SAPC frequently examines salbutamol’s pharmacology, including its mechanism of action (beta-2 adrenergic receptor agonism → bronchial smooth muscle relaxation), adverse effects (tremor, tachycardia, hypokalaemia with high doses), and the importance of using a spacer device with pMDIs to improve pulmonary deposition and reduce oropharyngeal deposition (and hence systemic absorption and local side effects such as oral candidiasis with inhaled corticosteroids).
Inhaled corticosteroids (ICS) such as budesonide (Pulmicort) and fluticasone (Flixotide) are the cornerstone of asthma controller therapy. They act locally to reduce airway inflammation, with minimal systemic absorption (bioavailability of inhaled corticosteroids is primarily from the lung, where they exert their anti-inflammatory effect; swallowed portions are subject to extensive first-pass metabolism, reducing systemic exposure). Beclomethasone and ciclesonide are also available; ciclesonide is a prodrug that is activated in the lung, potentially offering improved local selectivity.
Combination inhalers (ICS + LABA) such as Seretide (fluticasone/salmeterol) and Symbicort (budesonide/formoterol) are widely used for moderate-to-severe asthma and COPD in South Africa. Candidates should understand the complementary mechanisms: the inhaled corticosteroid reduces airway inflammation and reduces exacerbations, while the long-acting beta-agonist provides sustained bronchodilation.
Long-acting muscarinic antagonists (LAMAs) such as tiotropium (Spiriva) and glycopyrronium are used for COPD maintenance therapy. They block M3 muscarinic receptors on bronchial smooth muscle, preventing acetylcholine-mediated bronchoconstriction.
In South Africa, inhaled antibiotics such as tobramycin (Tobi) and colistin are used for chronic Pseudomonas aeruginosa colonisation in cystic fibrosis patients, and aztreonam lysine (Cayston) is available for the same indication. These drugs are administered via nebulisation and act locally in the airways, with minimal systemic absorption.
Systemic absorption via the pulmonary route: For drugs intended for systemic effect, the pulmonary route can offer significant bioavailability advantages. Insulin inhaled (Exubera, now discontinued; Afrezza, still available in some markets) demonstrated that large protein molecules could be absorbed systemically through the alveoli, though the formulation challenges and the large device size limited commercial success. In South Africa, no inhaled insulin product is currently marketed, but interest remains in this route for future protein and peptide delivery.
Critical analysis of pulmonary absorption: While the pulmonary route bypasses first-pass metabolism for systemically absorbed drugs, it has important limitations. Not all drugs are stable in the lung environment; some are metabolised by pulmonary enzymes (including CYP enzymes expressed in bronchial and alveolar epithelial cells). The large surface area and rich blood supply of the alveoli mean that systemically absorbed pulmonary drugs have a very rapid onset of effect — this is advantageous for inhaled sedatives (for procedural sedation or critical care ventilation) such as inhaled anaesthetic agents (sevoflurane, isoflurane) and potentially for inhaled opioids, but it also means that the pulmonary route is particularly unforgiving of dosing errors. The pulmonary route also exposes the lungs to high local drug concentrations, which can cause local adverse effects (inhaled corticosteroids causing oropharyngeal candidiasis and dysphonia; beta-agonists causing bronchial irritation; and preservatives or excipients in inhaler formulations potentially causing bronchospasm in sensitive individuals).
Bioavailability and Bioequivalence
Definitions and Clinical Significance
Bioavailability was defined earlier in this chapter as the fraction of administered drug that reaches the systemic circulation unchanged. It is a crucial pharmacokinetic parameter that determines the dose required to achieve a target plasma concentration when a particular route is used. Bioavailability is not a fixed property of a drug — it is influenced by the drug’s formulation, the route of administration, the patient’s physiology, and drug interactions.
Absolute bioavailability is determined by comparing the AUC after the test route to the AUC after an intravenous dose (which is the reference of 100% bioavailability). This comparison controls for elimination, isolating absorption as the variable. The absolute bioavailability of a drug after a specific extravascular route provides critical information for dose selection.
Relative bioavailability compares two non-intravenous formulations or routes of the same drug. It is used in bioequivalence studies to determine whether a generic product produces systemic exposure (Cmax and AUC) comparable to the brand product, and in formulation science to compare different dosage forms.
Bioequivalence is a regulatory concept (adopted by SAHPRA, the South African Health Products Regulatory Authority, formerly the Medicines Control Council) that two pharmaceutical products are considered bioequivalent if their rate and extent of absorption, as measured by Cmax and AUC, fall within specified acceptance limits (typically 80–125% of the reference product’s parameters, with 90% confidence intervals). Bioequivalence ensures that generic medicines produce clinically equivalent therapeutic effects to their brand-name equivalents and that different formulations of the same drug (such as modified-release products) are reliably interchangeable.
| Parameter | What it measures | Clinical relevance |
|---|---|---|
| Cmax | Peak plasma concentration | Onset of effect; risk of peak-related adverse effects |
| Tmax | Time to reach Cmax | Speed of onset |
| AUC (0→∞) | Total systemic exposure | Overall drug exposure; related to total pharmacological effect |
| Bioavailability (F) | Fraction reaching systemic circulation | Dose required; route selection |
Factors Influencing Bioavailability
A comprehensive understanding of the factors that determine bioavailability allows the pharmacist to predict, monitor, and manage therapeutic outcomes.
Physicochemical factors: Aqueous solubility, particle size, crystal form (polymorphism), salt form, and lipophilicity all influence the rate and extent of absorption and therefore bioavailability. The salt form of a drug can significantly affect its dissolution rate and solubility — for example, the phosphate salt of a drug may be more water-soluble than the free acid or base, leading to faster dissolution and potentially higher bioavailability.
Formulation factors: The dosage form itself (tablet, capsule, suspension, solution, modified-release) profoundly affects bioavailability. Immediate-release tablets may dissolve rapidly and be well-absorbed; enteric-coated tablets may have delayed absorption due to the coating delaying dissolution until the tablet reaches the small intestine; controlled-release formulations are designed to slow the release of drug, producing lower Cmax and longer Tmax, and they must be bioequivalent to the immediate-release reference in terms of AUC and steady-state behaviour. In South Africa, pharmacists dispensing generic products must be confident that the product is SAHPRA-approved and bioequivalent to the reference product.
Pharmacogenetic factors: Genetic polymorphisms in drug-metabolising enzymes and transporters can cause significant interindividual variation in bioavailability. CYP2D6 poor metabolisers convert codeine to morphine inefficiently, resulting in reduced analgesia from codeine and reduced bioavailabilty of the active moiety. CYP3A5 expressers (more common in individuals of African descent, including South African populations) may have higher clearance of CYP3A5 substrates such as tacrolimus, resulting in lower bioavailability and higher dose requirements. OATP1B1 polymorphisms (SLCO1B1 *5 variant, present in approximately 15–20% of individuals) reduce the hepatic uptake of statins such as simvastatin and rosuvastatin, altering their systemic exposure and their risk of myopathy.
Disease-related factors: Conditions that affect the gastrointestinal tract (coeliac disease, inflammatory bowel disease, short bowel syndrome, gastric surgery) can alter the surface area available for absorption and the expression of transporters and enzymes, changing bioavailability. Hepatic disease (cirrhosis) reduces first-pass metabolism and can increase oral bioavailability (as well as reducing drug clearance, compounding the risk of toxicity). Heart failure reduces splanchnic blood flow and can reduce the rate and extent of absorption of some drugs. Renal impairment does not directly affect oral bioavailability but can alter the clearance of drugs and their metabolites, changing net systemic exposure.
Drug interactions: As discussed earlier, drugs that induce or inhibit gastrointestinal or hepatic metabolising enzymes and transporters can significantly alter bioavailability. The classic example is rifampicin, which induces both intestinal CYP3A4 and P-gp, dramatically reducing the bioavailability of numerous drugs including ciclosporin, tacrolimus, warfarin, oral contraceptives, and many others. Inhibitors such as ketoconazole, erythromycin, and grapefruit juice have the opposite effect, increasing bioavailability and risking toxicity.
Special Considerations in Absorption Pharmacology
Drug Absorption in Specific Populations
Paediatric patients: The gastrointestinal physiology of infants and young children differs from adults in several ways that affect drug absorption. Gastric pH in neonates is near neutral (pH 6–7) at birth and decreases over the first 24–48 hours; by 2–3 years of age, gastric acid production reaches adult levels. This affects the absorption of pH-dependent drugs — for example, acid-labile drugs such as penicillin G may be better absorbed in neonates than in older children or adults. Gastric emptying is delayed in neonates (mean gastric emptying time of approximately 6–8 hours, compared to approximately 2–4 hours in adults), which can delay the absorption of oral drugs. Intestinal transit time is prolonged in infants, and the intestinal flora is not fully established, affecting bacterial metabolism of drugs such as chloramphenicol (where immature glucuronidation capacity in neonates leads to the grey baby syndrome). The skin of neonates is thinner and more permeable than adult skin, increasing the risk of systemic absorption from topical preparations and the risk of toxicity from otherwise safe topical agents.
Elderly patients: Age-related changes in gastrointestinal physiology include reduced gastric acid secretion, reduced intestinal surface area and microvilli density, reduced splanchnic blood flow, and altered intestinal motility (both delayed gastric emptying and, in some cases, accelerated transit). These changes can alter the bioavailability of drugs, though the magnitude of the effect varies considerably between individuals and between drugs. Of greater importance in the elderly is the reduction in hepatic and renal clearance, which changes the net systemic exposure more significantly than the absorption changes alone.
Pregnancy: Pregnancy induces numerous physiological changes that affect drug absorption. Progesterone reduces gastrointestinal motility and slows gastric emptying, potentially delaying oral drug absorption. Increased gastric pH (due to reduced acid secretion) can reduce the absorption of weakly acidic drugs. Increased plasma volume and cardiac output increase the apparent volume of distribution, potentially diluting drug concentrations. Increased hepatic and renal blood flow increase drug clearance. Increased body fat stores sequester lipophilic drugs, and increased fat stores can both prolong the terminal half-life of drugs like thiopental and potentially release stored drug back into the circulation postpartum. The placental transfer of drugs and the fetal exposure are discussed in the distribution chapter, but the absorption considerations are important for pregnant patients managing chronic conditions.
South African population context: South Africa has a genetically diverse population representing African, European, Indian, and mixed ancestry groups. Genetic polymorphisms in drug-metabolising enzymes and transporters are population-specific and can influence drug absorption and bioavailability. For example, CYP2D6 polymorphisms vary significantly between African populations and European populations; CYP3A5 is expressed in approximately 60–70% of individuals of African ancestry compared to approximately 20–30% of Europeans; NAT2 slow acetylator status is more common in certain Southern African population groups, affecting the metabolism of drugs such as isoniazid, hydralazine, and sulfonamides. Pharmacists practising in South Africa must appreciate that standard dosing regimens derived from studies in predominantly European populations may not apply uniformly to all South African patients, and that therapeutic drug monitoring (where available) is an important tool for individualising therapy.
Drug Absorption in Gastrointestinal Disease
Conditions that damage or alter the gastrointestinal mucosa can significantly affect drug absorption.
Coeliac disease causes villous atrophy in the small intestine, reducing the absorptive surface area. This can lead to reduced absorption of multiple drugs, particularly those requiring active transport mechanisms or with narrow absorption windows.
Inflammatory bowel disease (Crohn’s disease, ulcerative colitis) causes mucosal inflammation, ulceration, and scarring that can impair absorption. In acute flares, oral medications may be poorly absorbed and IV or IM routes may be preferred.
Short bowel syndrome (following extensive surgical resection) reduces the available surface area for absorption, and the remaining intestine may have altered motility and transporter expression.
Bariatric surgery (gastric bypass, sleeve gastrectomy, biliopancreatic diversion) has profound effects on drug absorption. Procedures that bypass the duodenum and proximal jejunum (Roux-en-Y gastric bypass) significantly reduce the absorption of some drugs that are absorbed in the bypassed segment, including certain formulations of oral contraceptives, calcium, iron, vitamin B12, and some extended-release formulations. Pharmacists should counsel bariatric surgery patients that their medications may need to be in liquid, chewable, or immediate-release formulations and that dose adjustments may be necessary.
Modified-Release Formulations and Absorption
Modified-release (MR) formulations are designed to alter the rate or site of drug absorption, providing therapeutic advantages over immediate-release formulations. They include extended-release (XR), sustained-release (SR), controlled-release (CR), and delayed-release (DR) formulations.
Extended-release formulations release drug over an extended period, allowing reduced dosing frequency (once or twice daily instead of three or four times daily), more stable plasma concentrations, reduced peak-trough fluctuations (lessening both peak-related adverse effects and trough-related therapeutic failures), and improved patient compliance.
Delayed-release formulations (such as enteric-coated tablets) are designed to release drug at a time or location distinct from the site of swallowing — for example, to protect the drug from gastric acid (as with enteric-coated aspirin or enteric-coated pancrelipase), to protect the stomach from the drug (as with enteric-coated diclofenac), or to target drug release to the intestine or colon.
Osmotic-controlled release oral delivery systems (OROS) use osmotic pressure to deliver drug at a controlled rate along the gastrointestinal tract. Examples include nifedipine OROS (Adalat LA) and methylphenidate OROS (Concerta). These systems are designed to provide steady drug release independent of gastrointestinal pH or motility.
South African pharmacy note: Generic versions of modified-release products must demonstrate bioequivalence to the reference product, but pharmacists should be aware that not all generic modified-release products are therapeutically equivalent. The Theriak system (used in South African pharmacy software) and other drug information resources can assist in identifying approved generic products. Switching between modified-release and immediate-release products is not automatically dose-equivalent and requires clinical assessment.
SAPC examination note: A common examination trap is to assume that a modified-release formulation can be crushed or split. Many modified-release formulations are specifically designed as single-unit systems (matrix tablets, osmotic pumps) that cannot be divided without destroying their modified-release properties, leading to dose-dumping (all the drug being released at once, potentially causing toxicity) or loss of the modified-release benefit. The examination may present a clinical scenario where a patient is unable to swallow a tablet and ask whether it can be crushed, requiring candidates to identify which formulations are safe to crush and which are not. The general rule is that unscored tablets, coated beads in capsules (unless the capsule can be opened and the beads swallowed without chewing), osmotic pump tablets, and enteric-coated tablets should not be crushed. Immediate-release scored tablets and some (but not all) extended-release tablets that are scored and designed for splitting may be divided.
Pharmacokinetic Modelling of Absorption
Zero-Order and First-Order Absorption
The rate at which a drug is absorbed can follow zero-order or first-order kinetics, with significant clinical consequences.
First-order absorption is the most common pattern for orally administered drugs. The rate of absorption is proportional to the amount of drug remaining at the absorption site: dA/dt = ka × A, where ka is the first-order absorption rate constant. This means that a larger dose produces a proportionally larger amount absorbed per unit time, but the fraction absorbed from the dose is constant (independent of dose size). Plasma concentrations rise rapidly initially and then more slowly as the absorption rate decreases and the elimination rate increases, producing the characteristic rising exponential curve.
Zero-order absorption occurs when the absorption process is saturated — the absorption site or formulation delivers drug at a constant rate regardless of the amount remaining. This is characteristic of constant-rate infusion (IV), transdermal patches, and some sustained-release formulations (particularly those based on osmotic pumps or matrix diffusion). Zero-order absorption produces a linear increase in plasma concentration until elimination begins to match the constant input rate, after which concentrations plateau.
Wagner-Nelson and Loo-Riegelman Methods
The Wagner-Nelson method is a pharmacokinetic deconvolution technique used to determine the absorption profile of a drug after oral administration, by separating the absorbed fraction from the disposition kinetics. It is applicable to one-compartment model drugs and involves calculating the fraction of the dose remaining to be absorbed at each time point, using the plasma concentration-time data. This method is useful for characterising the absorption phase and for comparing absorption profiles between formulations.
The Loo-Riegelman method extends this approach to two-compartment model drugs, accounting for the distribution phase. It requires multiple plasma concentration measurements during both the distribution and elimination phases to accurately resolve the absorption profile.
While these methods are primarily used in pharmacokinetic research and drug development, understanding them is useful for the SAPC examination because it illustrates how the overall plasma concentration-time profile is the net result of independent absorption and disposition processes, and how changes in either process can alter the clinical appearance of the drug’s pharmacokinetic profile.
Effect of Absorption Rate on Plasma Concentration-Time Profiles
The rate of absorption (ka) relative to the rate of elimination (ke) determines the shape of the plasma concentration-time curve and has important clinical implications.
When ka >> ke (very rapid absorption), the plasma concentration rises steeply to a high Cmax and then declines rapidly as elimination predominates. This pattern is associated with a rapid onset of effect but also a shorter duration of action and potentially higher risk of peak-related adverse effects.
When ka is similar to or slower than ke, the rise to Cmax is gradual, Cmax is lower, and the overall effect is smoother and more sustained, though the onset of action may be slower.
For drugs with very slow absorption (ka << ke), drug input is the rate-limiting step, and plasma concentrations rise slowly over many hours or days, potentially requiring a loading dose to achieve therapeutic concentrations within an acceptable timeframe.
Clinical Application: Absorption and Therapeutic Drug Monitoring
Therapeutic drug monitoring (TDM) integrates pharmacokinetic principles, including absorption parameters, to individualise drug therapy. TDM is most useful for drugs with a narrow therapeutic index, significant interindividual variability in pharmacokinetics, and a well-established relationship between plasma concentration and clinical effect or toxicity.
The interpretation of plasma drug concentrations in the context of absorption requires consideration of several factors. The timing of the blood sample relative to the last dose is critical — trough concentrations (Cmin, taken just before the next dose) are used for most drugs, as they best reflect steady-state concentrations. Peak concentrations (Cmax, taken at Tmax) are sometimes used for drugs with concentration-dependent toxicity. For drugs with long half-lives, steady-state concentrations are not reached until 4–5 half-lives have elapsed, and samples taken before steady state will underestimate the eventual steady-state concentration.
In South Africa, TDM is available for several important drugs where absorption and disposition variability are clinically significant. Aminoglycosides (gentamicin, amikacin) require monitoring of peak and trough concentrations, with targets adjusted for the type of infection (higher peaks for Gram-negative coverage in severe infections; lower targets to avoid nephrotoxicity and ototoxicity). Vancomycin monitoring targets an AUC/MIC ratio of ≥400 for optimal MRSA coverage, using either trough concentrations (target 10–15 mg/L for complicated infections) or, preferably, AUC-guided monitoring. Carbamazepine, phenytoin, valproic acid, and phenobarbital are monitored for both efficacy (minimum effective concentrations) and toxicity (concentrations associated with dose-related adverse effects). Ciclosporin and tacrolimus are monitored to ensure adequate immunosuppression while minimising nephrotoxicity. Methotrexate high-dose monitoring is essential to ensure adequate clearance before leucovorin rescue.
For drugs that undergo significant absorption variability, single plasma concentrations may be misleading. In such cases, AUC monitoring (using sparse sampling strategies and population pharmacokinetic models) provides a more accurate assessment of systemic exposure.
South African Regulatory and Clinical Context
SAHPRA and Biopharmaceutic Classification
The South African Health Products Regulatory Authority (SAHPRA) regulates the registration and bioequivalence requirements for pharmaceutical products in South Africa. For generic medicines to be approved, they must demonstrate bioequivalence to the reference (innovator) product, typically using a crossover study in healthy volunteers comparing Cmax and AUC parameters. For products where bioequivalence cannot be demonstrated using pharmacokinetic parameters (such as topical products, inhaled products, and some modified-release products), pharmacodynamic endpoints or clinical studies may be required.
SAHPRA’s adoption of the BCS-based biowaiver approach allows the waiver of in vivo bioequivalence studies for immediate-release solid oral dosage forms of highly soluble, highly permeable (BCS Class I) drugs, provided that the formulation contains no excipients known to affect absorption and that the drug is not a substrate for drug transporters. This approach accelerates the registration of generic products for well-characterised drugs and reduces the need for unnecessary clinical trials.
Essential Medicines List and Absorption Considerations
The South African Essential Medicines List (EML) and Standard Treatment Guidelines (STGs) incorporate absorption pharmacology considerations in their recommendations. For example, the adult and paediatric STGs for pneumonia recommend oral amoxicillin as first-line therapy for non-severe pneumonia, with the rationale that oral amoxicillin has good bioavailability (>80%) and is well-absorbed even in the presence of mild-to-moderate gastrointestinal illness. For severe pneumonia requiring hospitalisation, IV antibiotics are recommended, recognising that oral absorption may be unreliable in sick, febrile patients.
The tuberculosis treatment guidelines (SAHPRA/NICD) incorporate rifampicin’s powerful enzyme-inducing properties and its effect on the bioavailability of concomitant medicines. Patients on rifampicin who are also on antiretroviral therapy (ART), hormonal contraceptives, or warfarin require dose adjustments and/or additional monitoring to compensate for the enzyme induction. This is a particularly important issue in South Africa’s dual HIV-TB epidemic, where many patients are co-treated with rifampicin-based TB therapy and various antiretroviral agents.
South Africa’s integrated approach to TB and HIV is reflected in the fixed-dose combination (FDC) tablets used for both TB treatment (RHZE — rifampicin, isoniazid, pyrazinamide, ethambutol) and ART (tenofovir/lamivudine/efavirenz and others). The use of FDC tablets reduces pill burden and improves compliance, but pharmacists must understand the absorption characteristics of each component. Rifampicin is best absorbed on an empty stomach (bioavailability is reduced by approximately 30% when taken with food), while some ART components (efavirenz) can be taken with or without food (though taking with food, particularly a fatty meal, increases efavirenz exposure and may increase adverse effects).
Traditional Medicine Interactions with Absorption
Traditional medicine use is prevalent in South Africa. Herbal medicines used in traditional African healing, as well as complementary medicines available in pharmacies (such as St John’s wort, garlic supplements, ginkgo, Echinacea, and Asian traditional medicines), can significantly affect drug absorption and metabolism.
St John’s wort (Hypericum perforatum) induces CYP3A4, P-gp, and other drug-metabolising enzymes and transporters in the intestine and liver. It significantly reduces the plasma concentrations and efficacy of ciclosporin, tacrolimus, warfarin, digoxin, oral contraceptives (with case reports of contraceptive failure), antiretrovirals (including protease inhibitors and NNRTIs), methadone, and others. In South Africa’s HIV/TB treatment programmes, patients taking St John’s wort alongside their antiretroviral or immunosuppressant medications are at significant risk of treatment failure.
Garlic supplements (Allium sativum) have demonstrated CYP3A4 and P-gp inducing effects and can reduce plasma concentrations of drugs such as saquinavir (with a reduction of approximately 50% in the AUC of saquinavir observed in clinical studies).
Ginkgo biloba extracts can inhibit P-gp and may alter the pharmacokinetics of P-gp substrates including digoxin and some chemotherapeutic agents.
Echinacea has both inhibitory and inducing effects on CYP enzymes depending on the specific extract and duration of use, making its interaction profile complex and unpredictable.
Pharmacists in South Africa should routinely enquire about traditional and complementary medicine use during medication counselling, particularly for patients on medicines with narrow therapeutic indices, and should document and counsel on potential interactions.
Summary Tables
Absorption Mechanisms and Governing Factors
| Mechanism | Energy required | Gradient | Specificity | Example drugs |
|---|---|---|---|---|
| Passive diffusion | No | Concentration gradient | Non-specific | Most small molecules (paracetamol, ibuprofen) |
| Facilitated diffusion | No | Concentration gradient | High (transporter-specific) | Glucose, levodopa via LAT1 |
| Active transport | Yes (ATP) | Against gradient | High | Some peptides (valaciclovir via PEPT1) |
| Paracellular | No | Concentration gradient | Non-specific (pore-size limited) | Metformin, some peptides |
| Transcytosis | Yes (vesicular) | Non-specific | Low | Insulin, vaccines |
Routes of Administration and Absorption Characteristics
| Route | First-pass effect | Bioavailability range | Onset | Suitable for |
|---|---|---|---|---|
| Intravenous | None | 100% (by definition) | Immediate | Emergency drugs, drugs requiring precise control |
| Intramuscular | None (enters systemic directly) | 70–100% (formulation-dependent) | Rapid (minutes to hours) | Vaccines, hormones, depot formulations |
| Subcutaneous | None (enters systemic directly) | 70–100% (formulation-dependent) | Slower than IM | Insulin, biologics, peptides |
| Oral | Extensive (gut wall + hepatic) | 0–100% (highly variable) | Delayed (minutes to hours) | Most chronic therapies |
| Sublingual/Buccal | Minimal (bypasses liver) | Variable, often high | Rapid | Nitrates, some opioids, hormones |
| Rectal | Partial (50% bypass possible) | 50–80% (variable) | Variable | Antiemetics, analgesics, anticonvulsants |
| Transdermal | Minimal (direct systemic) | Variable (controlled by formulation) | Slow (hours) | Hormones, analgesics, nicotine |
| Pulmonary | Minimal (direct systemic) | Variable (device and technique dependent) | Rapid (for local effect) | Bronchodilators, steroids, anaesthetics |
| Topical | Minimal (primarily local) | Very low systemic | Local | Skin infections, inflammation |
pH Effects on Drug Absorption
| GI compartment | pH range | Weakly acidic drugs | Weakly basic drugs | Clinical note |
|---|---|---|---|---|
| Stomach | 1.5–3.5 | Rapidly absorbed (mostly unionised) | Poorly absorbed (mostly ionised) | Avoid antacids before weakly acidic drugs |
| Duodenum | 4.0–6.0 | Variable; less unionised | Better absorbed than in stomach | Most drug absorption occurs here |
| Jejunum/Ileum | 6.0–7.5 | Mostly ionised | More unionised; better absorbed | Largest surface area for absorption |
| Colon | 5.5–7.0 | Variable | Variable | Important for extended-release drug delivery |
| Rectum (lower) | ~7 (aqueous) | Variable | Variable | Bypasses first-pass if placed low |
SAPC Examination Preparation: Key Points and Common Pitfalls
The SAPC examination frequently tests absorption pharmacology through clinical case scenarios, calculation-based questions, and applied pharmacology questions. The following points represent the most frequently examined concepts and the areas where candidates most commonly err.
First-pass metabolism calculations and clinical implications are a perennial favourite in the SAPC examination. Candidates should be able to identify drugs with extensive first-pass metabolism from their known oral bioavailability values, understand why the oral dose must be higher than the IV dose for such drugs, and apply this understanding to clinical scenarios such as converting between oral and IV therapy (e.g., converting oral morphine to IV morphine, requiring a reduction in dose by approximately two-thirds to account for first-pass and oral bioavailability). The key pitfall is to assume that oral and IV doses are interchangeable without adjustment for bioavailability — they are not.
Bioavailability and bioequivalence questions may present a clinical scenario where a patient is switched between a brand-name and generic product, or between two generic products, and ask whether the switch is appropriate. Candidates must understand that SAHPRA-approved generic products have demonstrated bioequivalence (within 80–125% of the reference) and are therefore therapeutically interchangeable in most clinical situations. However, for drugs with narrow therapeutic indices (digoxin, phenytoin, warfarin, ciclosporin, lithium), careful monitoring is advised when switching between products, and patients should be counselled to maintain consistency with their usual brand where possible.
pH partition and food effect questions frequently involve predicting whether a drug’s absorption will be increased or decreased by a change in gastric pH (antacid administration, proton pump inhibitor therapy, H2 blocker therapy) or by food intake. Candidates should be able to apply Henderson-Hasselbalch principles to predict the direction of effect and should know the specific food-drug interactions that are clinically most important (grapefruit juice, dairy products with fluoroquinolones and tetracyclines, fatty meals with griseofulvin and halofantrine, timing of thyroid hormone replacement relative to calcium and iron supplements).
Transporter-mediated interactions are an increasingly examined area. Candidates should know the major P-gp substrates (digoxin being the most commonly tested) and the major P-gp inducers (rifampicin) and inhibitors (ketoconazole, erythromycin, verapamil) and should be able to predict the clinical consequence of co-administration. The interaction between rifampicin and ciclosporin or tacrolimus is particularly important in the South African transplant context.
Modified-release formulation questions frequently present a scenario where a patient has a nasogastric tube or is unable to swallow, and ask whether the medication can be crushed or dissolved. Candidates must be able to identify which formulations are unsuitable for crushing (enteric-coated, controlled-release, osmotic pump, unscored matrix tablets) and must appreciate the clinical consequences of inappropriate manipulation — dose-dumping from controlled-release formulations can cause life-threatening toxicity, while crushing enteric-coated tablets can destroy the enteric coating and expose the stomach to a drug intended for intestinal release, or expose the drug to gastric acid degradation, resulting in therapeutic failure.
Inhaler technique counselling is a uniquely important competency for pharmacists in South Africa, where the burden of asthma and COPD is high and access to pulmonologists is limited. Candidates should be able to demonstrate and counsel on the correct use of pMDIs (with and without spacers), DPIs (Turbohaler, Diskus, Accuhaler, Ellipta), and nebulisers, and should understand how incorrect technique leads to therapeutic failure. The SAPC has in recent years placed increased emphasis on this practical counselling competency.
Traditional medicine interactions are a growing area of concern in South African practice. Candidates should be able to identify the most clinically significant herbal interactions (St John’s wort with immunosuppressants, anticoagulants, and antiretrovirals being the most critical) and should be prepared to counsel patients on the risks of combining traditional remedies with prescription medicines.
Conclusion
Drug absorption is the gateway to systemic drug effect and is governed by a complex interplay of physicochemical properties, physiological mechanisms, anatomical factors, formulation design, transporter biology, and individual patient characteristics. A thorough understanding of absorption pharmacology is foundational to rational drug therapy — it informs the selection of the route and formulation of administration, the interpretation of plasma drug concentrations, the prediction and management of drug interactions, and the individualisation of therapy for specific patient populations. In the South African context, where the pharmacy profession carries significant responsibility for medication counselling, therapeutic monitoring, and public health interventions, the pharmacist’s understanding of absorption science is a critical clinical competency that directly affects patient outcomes.
Mastery of the principles covered in this chapter — membrane transport mechanisms, the pH partition hypothesis, first-pass and presystemic metabolism, transporter pharmacology, route-specific absorption characteristics, bioavailability and bioequivalence, formulation effects, and population-specific considerations — will equip the candidate for the SAPC examination and for the broader clinical challenges of pharmacy practice in South Africa.
References and further reading: Rang and Dale’s Pharmacology; Goodman & Gilman’s The Pharmacological Basis of Therapeutics; Applied Biopharmaceutics & Pharmacokinetics (Shargel and Yu); South African Medicines Formulary (SAMF); SAHPRA Guidelines for Bioequivalence Studies; South African Standard Treatment Guidelines (Primary Healthcare level, 2020–2024 editions); WHO Model Formulary.