Pharmacokinetics — Absorption, Distribution, Metabolism, and Excretion (ADME)

Pharmacokinetics describes what the body does to a drug. Understanding ADME processes is critical for rational dosing, predicting drug interactions, and optimizing therapy. For the SAPC examination, you must be able to apply pharmacokinetic principles to clinical scenarios and interpret pharmacokinetic parameters.

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Fundamental Concepts

Bioavailability (F)

Bioavailability is the fraction of an administered dose that reaches the systemic circulation unchanged, expressed as a fraction (f) or percentage (%).

• Absolute bioavailability compares the systemic exposure of the extravascular route to the intravenous route: F = AUCₒᵥ / AUCᵢᵥ
• Relative bioavailability compares two different formulations of the same drug

Factors affecting bioavailability:

Factor	Effect
First-pass metabolism	Reduces oral bioavailability (e.g., propranolol, morphine)
Aqueous solubility	Poorly soluble drugs have incomplete absorption
Particle size	Smaller particles → larger surface area → faster absorption
Formulation	Enteric coating, sustained-release → altered absorption
Gastric pH	Acidic drugs absorbed in stomach; basic drugs in intestine
Transporters (P-gp, OATP)	Can limit or enhance absorption

Key reference values:

• IV bolus: F = 100% (by definition)
• Oral solution: typically high F
• Tablet/capsule: variable, depends on formulation

Half-Life (t½)

Half-life is the time required for the plasma concentration to decrease by 50%.

• First-order elimination: t½ = 0.693 × Vd / CL
• Steady-state: reached after approximately 4–5 half-lives
• Clinical significance: determines dosing interval and time to steady state

Half-life	Steady-state time (approx.)	Clinical implication
4h	16–20h	QID dosing possible
12h	48–60h	BID dosing acceptable
24h	4–5 days	Once daily dosing feasible
48h	8–10 days	Loading dose may be needed

Volume of Distribution (Vd)

Vd is a theoretical volume that relates the total amount of drug in the body to the plasma concentration: Vd = Dose / C₀

Vd Range	Interpretation	Drug Examples
<10 L (~body water)	Primarily plasma/water	Heparin, warfarin (highly protein bound)
10–30 L	Blood and interstitial fluid	Many drugs distribute to total body water
>30 L	Tissue binding > plasma binding	Lithium, chloroquine, many lipophilic drugs
Very large	Extensive tissue sequestration	Ivermectin, tacrolimus

Clinical implication: A large Vd means the drug is largely outside the plasma compartment — dialysis will not effectively remove it.

Clearance (CL)

Clearance is the volume of plasma cleared of drug per unit time (L/h or mL/min).

• Hepatic clearance: CLₕ = Q × (Clᵤᵢ / (Q + Clᵤᵢ)) where Q = hepatic blood flow, Clᵤᵢ = intrinsic clearance
• Renal clearance: CLᵣ = (U × V) / P where U = urine concentration, V = urine flow rate, P = plasma concentration

Total clearance: CL = CLₕ + CLᵣ (+ other routes)

Loading Dose and Maintenance Dose

Loading dose = (Vd × Cp,target) / F Maintenance dose rate = (CL × Cp,target) / F

A loading dose is used when the therapeutic concentration must be achieved quickly. It is typically needed for drugs with long half-lives.

Example calculation:

• Target concentration: 10 mg/L
• Vd: 50 L
• Bioavailability: 0.8
• Loading dose = (50 × 10) / 0.8 = 625 mg

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Absorption

Routes of Administration

Route	Bioavailability	Onset	Notes
Intravenous (IV)	100% (direct to bloodstream)	Immediate	Bypasses absorption; all drug available
Intramuscular (IM)	Variable (depends on formulation)	Rapid	Depot formulations; absorption via muscle capillaries
Subcutaneous (SC)	Variable; slightly slower than IM	Rapid	For proteins/peptides; good absorption
Oral (PO)	Variable; subject to first-pass	Slower	Most common; affected by gastric emptying, food
Rectal (PR)	Variable; ~50% avoids first-pass	Variable	Partially bypasses liver; useful if oral not possible
Transdermal	Low but sustained	Slow	Patches; fentanyl, nicotine, hormones
Inhaled	Variable	Rapid (for local)	For respiratory drugs; systemic via alveolar absorption
Topical	Low systemic absorption	Local only	Skin, eye; limited systemic toxicity

Mechanisms of Drug Absorption

1. Passive diffusion — most drugs; follows concentration gradient; no energy required. Depends on: lipophilicity, ionization state, surface area, concentration gradient.
2. Carrier-mediated transport — active or facilitated; for structurally specific compounds (e.g., levodopa via LAT1 transporter).
3. Endocytosis/exocytosis — for large molecules (e.g., insulin, enoxaparin).
4. Paracellular route — through tight junctions; limited; hydrophilic drugs only.

Factors Affecting Oral Absorption

Gastric emptying rate: Faster emptying → faster absorption in small intestine. Prokinetic agents (metoclopramide) accelerate; anticholinergics delay.

Intestinal transit time: Longer small intestinal transit → more absorption for drugs with absorption windows (e.g., metformin, gabapentin).

Food effects:

Type of drug	Food effect	Mechanism
Fat-soluble drugs	Increased absorption	Fat stimulates bile secretion
Drugs requiring acidity	Variable	Food buffers gastric pH
Drugs with absorption windows	Decreased if taken with food	Food delays gastric emptying
MAO inhibitors	Dietary tyramine interactions	—
Rifampicin	Decreased absorption	Induction of transporters

Drug interactions affecting absorption:

• Antacids (raise gastric pH) → decreased absorption of weakly acidic drugs
• Chelation (tetracyclines + calcium, iron) → form insoluble complexes
• P-gp inhibitors (ketoconazole, erythromycin) → increased absorption of P-gp substrates

SAPC Note on Absorption

For the SAPC examination, be particularly aware of drugs with significant first-pass metabolism (propranolol, morphine, lidocaine, nitrates, testosterone) — their oral bioavailability is low and variable, and dose adjustments are required when switching between routes.

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Distribution

Protein Binding

Most drugs bind to plasma proteins, primarily albumin and α₁-acid glycoprotein (AAG):

• Albumin: binds acidic and neutral drugs (warfarin, benzodiazepines, NSAIDs)
• α₁-acid glycoprotein: binds basic drugs (propranolol, lignocaine, quinidine)
• Only free (unbound) drug is pharmacologically active — it distributes, is metabolized, and exerts effects

Displacement interactions: When two drugs compete for the same binding site, the more tightly bound drug displaces the other, increasing the free fraction of the displaced drug.

Drug	Primary binding protein
Warfarin	Albumin
Phenytoin	Albumin
Quinolones	Albumin
Sulfonamides	Albumin
Quetiapine	α₁-acid glycoprotein

Clinical significance of displacement:

• Warfarin + sulfonamides → increased free warfarin → bleeding risk
• Valproic acid + phenytoin → displacement → phenytoin toxicity

Tissue Distribution

Blood-brain barrier (BBB):

• Tight junctions between endothelial cells
• Only lipophilic, low molecular weight drugs cross effectively
• Efflux transporters (P-gp, BCRP) limit CNS penetration
• Examples of CNS-penetrating drugs: morphine, diazepam, fluoxetine, chlorpromazine
• Poorly penetrating: heparin, gentamicin, most proteins/peptides

Placental transfer:

• Most drugs cross the placenta to some degree
• Lipophilic drugs cross most readily
• FDA Pregnancy Categories (historical): A (safest) → B → C → D → X (contraindicated)
• SAHPRA requires careful risk-benefit assessment

Apparent Volume of Distribution — Extended Interpretation

Drug	Vd (L/kg)	Interpretation
Warfarin	0.1–0.2	Mostly confined to plasma (highly protein bound)
Digoxin	3–5	Large Vd → tissue binding → monitor levels, avoid toxicity
Chloroquine	100–300	Extreme tissue sequestration
Lithium	0.6–0.9	Vd approximates total body water

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Metabolism

Phase I Reactions (Functionalization)

Phase I introduces or reveals a functional group through oxidation, reduction, or hydrolysis. Primarily mediated by the cytochrome P450 (CYP) enzyme system.

CYP enzymes relevant to pharmacy:

Enzyme	Substrates	Inducers	Inhibitors
CYP3A4	Most drugs (~50%); midazolam, simvastatin, clarithromycin, amiodarone	Rifampicin, phenytoin, carbamazepine	Ketoconazole, erythromycin, grapefruit juice
CYP2D6	Beta-blockers, antidepressants, codeine (to morphine), tramadol	Few (dexamethasone modest)	Quinidine, fluoxetine, paroxetine
CYP2C19	PPIs, clopidogrel (activation), diazepam, phenytoin	Rifampicin	Omeprazole, fluconazole, ticlopidine
CYP2C9	S-warfarin, NSAIDs, phenytoin, sulphonylureas	Rifampicin	Fluconazole, metronidazole
CYP1A2	Theophylline, clozapine, caffeine, olanzapine	Smoking, carbamazepine	Ciprofloxacin, fluvoxamine

Important pharmacogenetic considerations:

• CYP2D6 poor metabolizers: cannot convert codeine to morphine → no analgesic effect
• CYP2C19 poor metabolizers: reduced activation of clopidogrel → increased cardiovascular events
• CYP2C9 poor metabolizers: warfarin sensitivity → lower doses required

Phase II Reactions (Conjugation)

Phase II adds endogenous substances (glucuronic acid, sulphate, glutathione, acetate, amino acids) to make the drug more water-soluble and facilitate excretion.

Reaction	Substrate example	Outcome
Glucuronidation	Paracetamol, morphine, diazepam	UDP-glucuronosyltransferases (UGT)
Sulphation	Paracetamol (alternative pathway), oestrogens	Sulfotransferases
Acetylation	Isoniazid, hydralazine, sulfonamides	N-acetyltransferases (NAT)
Glutathione conjugation	Paracetamol (toxic metabolite neutralization)	Glutathione S-transferases

First-pass metabolism: After oral administration, drugs absorbed from the GI tract travel via the portal vein to the liver before reaching the systemic circulation. A drug with extensive first-pass metabolism will have low oral bioavailability (F << 1).

SAHPRA and SAPC note: Be aware that many traditional medicines used in South Africa can induce or inhibit CYP enzymes (e.g., St. John’s wort, garlic, ginkgo, certain traditional herbal remedies), leading to drug interactions.

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Excretion

Renal Excretion

Renal excretion involves three processes:

1. Glomerular filtration (GFR ~120 mL/min):

• Only free drug is filtered (protein-bound drug stays in plasma)
• Modified by renal function
• Creatinine clearance (CrCl) used to estimate GFR
• Cockcroft-Gault equation: CrCl = [(140 − age) × weight (kg)] / [72 × serum creatinine (μmol/L)] (×0.85 for females)

2. Tubular secretion (active, carrier-mediated):

• Occurs in proximal tubule
• Competes for transport carriers (organic anion transporter, organic cation transporter)
• Examples: penicillins, cephalosporins, diuretics, metformin
• Drug interactions: Probenecid inhibits secretion of penicillins and cefoxitin

3. Tubular reabsorption (passive):

• Occurs primarily in distal tubule
• Lipophilic drugs are reabsorbed (reducing excretion)
• Urine pH influences reabsorption of weakly acidic/weakly basic drugs
  • Acidification (NH₄Cl): increases excretion of weak bases
  • Alkalinization (NaHCO₃): increases excretion of weak acids (e.g., salicylate overdose)

Biliary and Fecal Excretion

• Some drugs (especially those with molecular weight > 500 Da) are excreted in bile
• Enterohepatic circulation: drug is excreted in bile → intestinal bacteria deconjugate → reabsorption → back to liver
• Examples: rifampicin, ethinyloestradiol, chloramphenicol
• Clinical consequence: interruption of enterohepatic circulation (e.g., by antibiotics) can reduce drug exposure

Other Routes of Excretion

Route	Notes
Pulmonary	Volatile anesthetics, alcohol
Salivary	Drugs excreted into saliva; useful for monitoring (e.g., carbamazepine)
Breast milk	Depends on pKa, protein binding, lipophilicity; many drugs are contraindicated
Sweat	Certain drugs (antimicrobials, some illicit drugs)

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Pharmacokinetic Compartmental Models

One-Compartment Model

Assumes drug distributes instantaneously throughout the body. Concentration declines mono-exponentially after absorption and distribution cease.

• Elimination: C = C₀ × e^(−kₑt)
• Half-life: t½ = 0.693 / kₑ
• Example drugs: Aminoglycosides (gentamicin), lithium

Two-Compartment Model

Distinguishes central compartment (plasma) and peripheral compartment (tissues). Useful for drugs that redistribute over time.

• Alpha phase (distribution): initial rapid decline
• Beta phase (elimination): slower terminal decline
• Example drugs: Thiopentone, digoxin, many antihypertensives

Michaelis-Menten Kinetics (Non-linear)

At high concentrations, metabolic and excretory pathways become saturated → zero-order kinetics.

• Equation: dC/dt = −(Vₘₐₓ × C) / (Kₘ + C)
• Clinical examples: Phenytoin, methanol, ethanol, aspirin at high doses
• Sign: half-life increases as dose increases (opposite of first-order kinetics)
• Important for: phenytoin loading and maintenance dosing to avoid toxicity

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SAPC Examination Tips

1. Half-life calculations — Be able to calculate when steady state will be reached and how much of a loading dose is needed. Steady state is reached in ~4–5 half-lives regardless of dose or dosing interval.
2. Bioavailability and first-pass — Identify drugs with low oral bioavailability (propranolol ~25%, morphine ~35%, lidocaine oral ~35%) and understand why they cannot be given orally.
3. Protein binding and interactions — Know which drugs are highly protein-bound and can displace each other. The classic exam question pairs warfarin with a displacing drug.
4. CYP450 interactions — Be able to identify the major CYP enzymes, their substrates, inducers, and inhibitors. The rifampicin-ketoconazole pair is a classic exam example.
5. Renal dosing — Estimate renal function using Cockcroft-Gault. For drugs with narrow therapeutic indices (gentamicin, vancomycin, digoxin), adjusted dosing is essential.
6. Enterohepatic circulation — Understand how interruption (e.g., by cholestyramine, antibiotics) affects drug levels.

Common Examination Trap

A common SAPC trap is to confuse half-life with time to steady state. Remember: the time to steady state depends ONLY on the half-life, not on the dose or dosing frequency. Doubling the dose does NOT make steady state arrive faster — it just raises the steady-state concentration. Similarly, a drug with a 48-hour half-life will take 8–10 days to reach steady state regardless of the dose given.