Pharmacokinetics: Metabolism and Excretion covers pharmacokinetics — metabolism and excretion for INI CET (AIIMS PG).
Biotransformation (Metabolism): Chemical conversion of a drug into a more water-soluble form for excretion.
Primary Site: Liver (most drugs)
- Also: GI mucosa (first-pass), kidney, lung, plasma (pseudocholinesterase)
Two Phases of Metabolism:
Phase I — Functionalization Reactions (CYP450 system):
- Introduces or exposes a functional group (-OH, -NH₂, -SH, -COOH)
- Microsomal mixed-function oxidase system (CYP450): Most important
- CYP enzymes: Superfamily — CYP1A2, CYP2D6, CYP3A4 (most abundant — metabolizes ~50% of drugs)
- Reactions: Oxidation (most common), reduction, hydrolysis
- Inducers (↑CYP activity): Rifampin, phenytoin, carbamazepine, phenobarbital, chronic alcohol, smoking
- Inhibitors (↓CYP activity): Cimetidine, erythromycin, ketoconazole, grapefruit juice, quinidine
- First-pass effect: Significant hepatic metabolism before systemic circulation
Phase II — Conjugation Reactions:
- Covalent attachment of endogenous substrate (glucuronic acid, sulfate, glutathione, acetyl, methyl, amino acids)
- Glucuronidation (UGT — most common): Phase II for drugs with -OH, -COOH, -NH₂ groups; bilirubin pathway
- Sulfation: Steroid hormones, paracetamol (forms non-toxic conjugates)
- Acetylation: Isoniazid, hydralazine, procainamide (slow vs fast acetylators)
- Glutathione conjugation: Detoxification of electrophilic metabolites (NAPQI from paracetamol overdose — N-acetylcysteine replenishes glutathione)
First-Order vs Zero-Order Kinetics:
- First-order kinetics (most drugs): Rate of elimination is proportional to drug concentration (constant fraction per unit time)
- Half-life (t½) is constant
- C = C₀ × e^(-kt); t½ = 0.693/k
- Zero-order kinetics: Rate of elimination is constant regardless of concentration (saturation at high concentrations)
- Examples: Phenytoin (at therapeutic levels), aspirin (high dose), ethanol
- t½ increases as concentration increases (not constant)
Excretion:
- Renal excretion (most important for polar drugs):
- Glomerular filtration (all unbound drugs): GFR ~125 mL/min; creatinine clearance estimates GFR
- Tubular secretion (active transport — organic anion/cation transporters): Secretes drugs from peritubular capillaries into tubular lumen; e.g., penicillin, probenecid (inhibits tubular secretion of penicillins)
- Tubular reabsorption (passive — pH-dependent): Ionized drugs in alkaline/acidic urine are trapped and reabsorbed
- pH-dependent excretion: Acidic drugs (salicylates, barbiturates) → excreted faster in alkaline urine (trapped as ionized form); alkaline drugs (amphetamines, morphine) → excreted faster in acidic urine
- Hepatic/biliary excretion: Some drugs excreted in bile → enter intestine → some reabsorbed (enterohepatic circulation → prolonged action)
⚡ Exam Tip for INI CET (AIIMS PG): Paracetamol overdose → depletes glutathione → NAPQI (toxic metabolite) accumulates → hepatic necrosis. Treatment: N-acetylcysteine (NAC) — replenishes glutathione and directly conjugates NAPQI.