14.3 Metabolism & Elimination

Phase I and Phase II Metabolism

Biotransformation converts lipophilic drugs into more polar, readily excreted products, mainly in the liver.

• Phase I reactions — oxidation, reduction and hydrolysis — introduce or expose a reactive group. Most are catalysed by the cytochrome P450 (CYP450) superfamily in hepatocyte smooth endoplasmic reticulum. Products may be active, inactive or occasionally toxic (e.g., paracetamol oxidation to the hepatotoxic metabolite NAPQI).
• Phase II reactions — conjugation of the drug or its phase I metabolite with a large polar group: glucuronidation (the most common), sulfation, acetylation, methylation and glutathione conjugation. Products are almost always inactive and water-soluble. Acetylation shows a clinically important polymorphism: slow acetylators (low NAT2 activity) are prone to isoniazid-induced neuropathy and to drug-induced lupus from hydralazine and procainamide.

Major CYP450 isoforms — the exam table

Memory hooks: grapefruit juice and azoles inhibit 3A4 (substrate levels rise); rifampicin, carbamazepine, phenytoin and St John's Wort are broad inducers (substrate levels fall — the mechanism behind oral contraceptive and warfarin failure with rifampicin); smoking induces 1A2, so smokers need higher theophylline and clozapine doses, and quitting smoking on an unchanged dose can cause toxicity.

Prodrugs

Prodrugs are inactive (or much less active) compounds that require metabolism for activation:

• Codeine → morphine by CYP2D6. Poor metabolizers get little analgesia; ultrarapid metabolizers can generate dangerous morphine levels (fatal respiratory depression has been reported in breastfed infants of ultrarapid-metabolizer mothers).
• Clopidogrel → active thiol metabolite, largely via CYP2C19. Poor metabolizers — and patients co-prescribed CYP2C19 inhibitors such as omeprazole — get a blunted antiplatelet effect.
• Levodopa crosses the blood-brain barrier (unlike dopamine) and is decarboxylated to dopamine centrally; co-formulated carbidopa or benserazide blocks its peripheral conversion.
• Valaciclovir → aciclovir by hydrolysis, giving roughly 3–5 times the oral bioavailability of aciclovir itself.

Enzyme Induction versus Inhibition — the time course

• Induction requires synthesis of new enzyme protein, so onset and offset are slow — days to weeks. Rifampicin takes about a week to reach full effect and two or more weeks to wear off after stopping. Carbamazepine autoinduces its own metabolism: concentrations fall over the first 2–4 weeks on a fixed dose, so it is started low and titrated upwards.
• Inhibition is usually rapid — as soon as the inhibitor reaches the enzyme. Clarithromycin can raise simvastatin levels within days (rhabdomyolysis risk), and grapefruit juice acts on intestinal CYP3A4 with the first glass. Mechanism-based (irreversible) inhibitors — macrolides, grapefruit juice — persist until new enzyme is synthesized, so their effect outlasts the inhibitor's presence in plasma.

Clinical reflex for the exam: when an interacting drug is started or stopped, ask which way the substrate level moves and how fast. Induction questions are the classic trap because the interaction only appears after a delay — warfarin control, for example, collapses a week or two after rifampicin is begun, not on day one.

Renal Elimination

Three processes determine renal clearance:

1. Glomerular filtration — free (unbound) drug of low molecular weight is filtered; protein-bound drug is not. Filtration tracks GFR (~120 mL/min in healthy young adults), which is why renally cleared drugs need dose adjustment when eGFR falls.
2. Active tubular secretion — organic anion (OAT) and cation (OCT) transporters in the proximal tubule actively secrete drugs regardless of protein binding. Secretion is saturable and competitive: probenecid blocks penicillin secretion (used historically to prolong penicillin action) and raises levels of methotrexate and many antivirals.
3. Passive tubular reabsorption — lipophilic, unionized drug is reabsorbed from the tubule. Because reabsorption is pH-dependent, manipulating urine pH changes elimination of weak electrolytes: urinary alkalinization with sodium bicarbonate ionizes salicylate (a weak acid) in the tubule, trapping it in urine and accelerating elimination in aspirin overdose — ion trapping in action.

Biliary Excretion and Enterohepatic Recycling

Larger, polar drugs and conjugated metabolites (often glucuronides, molecular weight above roughly 300–500) are excreted into bile. Gut bacteria can hydrolyse the conjugates, releasing active drug that is reabsorbed — enterohepatic recycling — which prolongs half-life and can produce a second plasma peak. Examples: ezetimibe (recycling sustains its cholesterol-lowering effect), mycophenolate (second peak at ~6–12 hours), and some oral contraceptive steroids (the classic teaching that broad-spectrum antibiotics reduce enterohepatic recycling and contraceptive efficacy — the evidence is weak, but it remains a standard exam point).

Clearance and Extraction Ratio

Clearance (CL) is the volume of plasma irreversibly cleared of drug per unit time:

CL = k × Vd, where k = 0.693 ÷ t½; and CL_total = CL_hepatic + CL_renal (+ other minor routes)

Worked example: a drug with t½ = 4 h and Vd = 40 L:

1. k = 0.693 ÷ 4 = 0.173 h⁻¹
2. CL = 0.173 × 40 ≈ 6.9 L/h

Clearance (not half-life) sets the maintenance dose: maintenance dose rate = CL × target Css ÷ F — for a target steady-state concentration of 15 mg/L and F = 1, that is 6.9 × 15 ≈ 104 mg/h.

The hepatic extraction ratio (E) predicts what controls hepatic clearance:

• High-extraction drugs (E > 0.7) — propranolol, lidocaine, morphine, GTN: clearance is flow-limited (depends on hepatic blood flow), shows a large first-pass effect, and falls sharply with portosystemic shunting or hepatic congestion.
• Low-extraction drugs (E < 0.3) — warfarin, phenytoin, theophylline, diazepam: clearance is capacity-limited (depends on enzyme activity and free fraction), so it is sensitive to enzyme induction, inhibition and hypoalbuminemia.