Drug metabolism
Drug metabolism: phase I and II, CYP450 inducers and inhibitors, pharmacogenomics
Phase I and II reactions, cytochrome P450, prodrugs, toxic metabolites, enzyme inducers and inhibitors, and pharmacogenomics for FCPS Part 1. Explains why interactions raise or lower drug levels and which patients react unusually.
Why drugs are metabolised
- Lipid-soluble drugs are filtered by the kidney but then reabsorbed, so they would stay in the body for a very long time. Metabolism, mainly in the liver, makes them more polar and water-soluble so they can be excreted in urine or bile.
- The enzymes sit in the smooth endoplasmic reticulum of hepatocytes (the "microsomal" enzymes), the same organelle that handles steroid metabolism.
- Metabolic capacity falls with advanced liver disease, old age and reduced hepatic blood flow (heart failure), so drugs that depend on hepatic clearance accumulate. Metabolism also occurs in the gut wall, lungs, kidney and plasma (esterases that break down suxamethonium and remifentanil).
Phase I and phase II
| Feature | Phase I | Phase II |
|---|---|---|
| What happens | Alters or unmasks a functional group (–OH, –NH2, –SH) | Conjugates the drug or its phase I product with a large polar molecule |
| Reactions | Oxidation, reduction, hydrolysis | Glucuronidation (commonest), sulphation, acetylation, methylation, glutathione conjugation |
| Main enzymes | Cytochrome P450, alcohol dehydrogenase, esterases, MAO | UGT, N-acetyltransferase, glutathione S-transferase, TPMT |
| Product | May be active, inactive or toxic | Usually inactive and readily excreted |
| Ageing and liver disease | Declines | Relatively preserved |
- Clinical result: in the elderly or in liver disease, benzodiazepines that need only phase II glucuronidation (lorazepam, oxazepam, temazepam) are safer than diazepam, which has long-acting phase I metabolites.
- Neonates have immature glucuronidation (grey baby syndrome with chloramphenicol, neonatal jaundice).
Prodrugs and toxic metabolites
- Prodrugs need metabolism to work: enalapril (to enalaprilat), clopidogrel (CYP2C19), codeine (to morphine by CYP2D6), levodopa, azathioprine (to 6-mercaptopurine), cyclophosphamide, prednisone, valaciclovir.
- Toxic metabolites formed by P450 in the smooth ER: paracetamol to NAPQI (detoxified by glutathione; acetylcysteine replenishes it), carbon tetrachloride to the trichloromethyl free radical, bromobenzene epoxides, methanol to formic acid, cyclophosphamide to acrolein. All damage centrilobular (zone 3) hepatocytes, where P450 is richest.
Cytochrome P450 enzymes
| Enzyme | Typical substrates |
|---|---|
| CYP3A4 (about half of all drugs) | Statins, ciclosporin, tacrolimus, calcium channel blockers, macrolides |
| CYP2D6 | Codeine, tamoxifen, many antidepressants and beta-blockers |
| CYP2C9 | Warfarin, phenytoin, NSAIDs |
| CYP2C19 | Clopidogrel, proton pump inhibitors |
| CYP1A2 | Theophylline, clozapine; induced by smoking |
| CYP2E1 | Ethanol, paracetamol; induced by chronic alcohol |
Inducers and inhibitors
| Feature | Enzyme inducers | Enzyme inhibitors |
|---|---|---|
| Examples | Carbamazepine, phenytoin, phenobarbital, rifampicin, St John's wort, chronic alcohol, smoking, griseofulvin | Clarithromycin, erythromycin, azole antifungals, cimetidine, ciprofloxacin, sodium valproate, isoniazid, amiodarone, ritonavir, grapefruit juice, metronidazole, acute alcohol |
| Mechanism | More enzyme is synthesised | Existing enzyme is blocked |
| Onset | Slow, 1–2 weeks (and slow offset) | Rapid, within days |
| Effect on other drugs | Lower levels: contraceptive failure, low INR on warfarin, transplant rejection, osteomalacia | Higher levels: warfarin bleeding, statin myopathy, theophylline toxicity (ciprofloxacin, erythromycin, cimetidine), ciclosporin toxicity |
- Stopping an inducer matters too: when a smoker on clozapine or theophylline quits, CYP1A2 activity falls over days and drug levels rise towards toxicity, so doses are reduced and levels checked.
- Ritonavir is used deliberately as a CYP3A4 inhibitor to boost other protease inhibitors. Allopurinol inhibits xanthine oxidase and so raises azathioprine toxicity.
- Not every interaction is metabolic: sucralfate binds other drugs in the gut (cimetidine, ciprofloxacin, digoxin), so doses are separated by about 2 hours.
Transporter interactions: amiodarone and digoxin
- Amiodarone inhibits P-glycoprotein (and reduces renal and non-renal clearance), so digoxin levels roughly double. When amiodarone is started, halve the digoxin dose and check levels. Amiodarone also inhibits warfarin metabolism (CYP2C9), so check the INR. Its very long half-life means interactions persist for months after stopping.
Pharmacogenomics
| Inherited variation | Consequence |
|---|---|
| Slow acetylators (N-acetyltransferase 2; about half of South Asians) | Isoniazid neuropathy and hepatotoxicity; drug-induced lupus with hydralazine, procainamide, isoniazid |
| Pseudocholinesterase deficiency | Prolonged apnoea after suxamethonium or mivacurium |
| G6PD deficiency | Haemolysis with primaquine, dapsone, sulphonamides, nitrofurantoin, rasburicase |
| CYP2D6 ultra-rapid | Codeine gives too much morphine (respiratory depression in children and breastfed infants) |
| CYP2C19 poor | Clopidogrel fails to activate |
| CYP2C9 and VKORC1 variants | Different warfarin dose needs |
| TPMT deficiency | Severe myelosuppression with azathioprine and 6-mercaptopurine; test first |
| DPD deficiency | 5-fluorouracil toxicity |
| HLA-B*15:02 | Carbamazepine Stevens–Johnson syndrome (South-East Asians) |
| HLA-B*57:01 | Abacavir hypersensitivity |
| RYR1 mutation | Malignant hyperthermia with volatile anaesthetics and suxamethonium |
| Acute porphyria | Attacks triggered by enzyme inducers |
- Excretion: renal filtration, active tubular secretion (penicillin, methotrexate; probenecid competes and prolongs penicillin), reabsorption; biliary excretion with enterohepatic recycling; lungs for volatile anaesthetics.
Remember Inducers act slowly and lower levels; inhibitors act fast and raise them.
Exam trap Starting amiodarone in a patient on digoxin: halve the digoxin and check the level.
Exam trap In the elderly choose a benzodiazepine that needs only phase II (lorazepam, oxazepam, temazepam).
How FCPS asks about this
- Difference between phase I and phase II: phase I alters functional groups (mainly P450 oxidation); phase II conjugates.
- Organelle where paracetamol, carbon tetrachloride and bromobenzene become toxic: smooth ER (cytochrome P450).
- Digoxin patient starting amiodarone: halve the digoxin dose and check levels.
- Enzyme inducer examples: carbamazepine, phenytoin, phenobarbital, rifampicin; inhibitors include macrolides, azoles, cimetidine and valproate.
- Theophylline metabolism decreased by: ciprofloxacin, erythromycin or cimetidine.
- Drug-induced lupus with hydralazine: slow acetylator.
- Prolonged apnoea after suxamethonium: pseudocholinesterase deficiency; TPMT must be checked before azathioprine.
Test yourself on this topic
5 of the 29 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A man with epilepsy controlled on phenytoin starts isoniazid for tuberculosis. Two weeks later he has nystagmus, ataxia and slurred speech. What explains this?
Answer: Isoniazid inhibits phenytoin metabolism
Isoniazid inhibits cytochrome P450 enzymes (especially CYP2C19 and 2C9) that metabolise phenytoin. Because phenytoin has saturable (zero-order) kinetics, a small fall in metabolism causes a large rise in level and toxicity: nystagmus, ataxia, dysarthria and confusion. The effect is greatest in slow acetylators. Rifampicin, given with isoniazid, induces enzymes and can partly offset this, so levels must be monitored.
Isoniazid interactions
- Isoniazid: enzyme inhibitor
- Raises phenytoin levels
- Worse in slow acetylators
- Rifampicin: enzyme inducer
Remember Isoniazid inhibits; rifampicin induces.
Exam trap Phenytoin's zero-order kinetics magnify small changes in metabolism.
Why the other options are wrong
- Isoniazid induces liver enzymes Rifampicin induces; isoniazid inhibits.
- Isoniazid causes cerebellar degeneration Not a recognised effect.
- Pyridoxine deficiency Causes neuropathy, not this cerebellar picture.
- Phenytoin blocks isoniazid acetylation Not the mechanism.
A man on digoxin for atrial fibrillation starts amiodarone. What should happen to his digoxin dose?
Answer: Halve it and check levels
Amiodarone (also verapamil, quinidine, clarithromycin) inhibits P-glycoprotein and reduces digoxin clearance, so digoxin levels can roughly double. The digoxin dose is usually halved with monitoring of levels and for toxicity: nausea, visual changes, bradycardia and arrhythmias. Hypokalaemia, hypomagnesaemia, hypercalcaemia and renal impairment also raise toxicity.
Digoxin interactions
- Raise level: amiodarone, verapamil
- Mechanism: P-glycoprotein inhibition
- Halve the dose, check levels
- Toxicity worse with low K⁺
Remember Amiodarone doubles digoxin.
Exam trap Amiodarone also raises warfarin effect; check the INR.
Why the other options are wrong
- Double it to keep rate control Would cause toxicity.
- Leave it unchanged Levels rise, risking toxicity.
- Stop digoxin permanently Not necessary.
- Change to IV digoxin Does not solve the interaction.
A COPD patient stable on oral theophylline stops smoking. A few weeks later he develops nausea, palpitations and tremor. Why?
Answer: Loss of CYP1A2 induction
Theophylline has a narrow therapeutic index (about 10–20 mg/L). It inhibits phosphodiesterase (raising cAMP) and blocks adenosine receptors. It is metabolised by CYP1A2. Polycyclic hydrocarbons in cigarette smoke induce CYP1A2, so smokers need higher doses; on stopping, clearance falls and levels rise. Levels also rise with enzyme inhibitors (ciprofloxacin, erythromycin, clarithromycin, cimetidine), heart failure, liver disease. Toxicity: nausea, vomiting, tachyarrhythmias, hypokalaemia and seizures.
Theophylline
- Narrow index (10–20 mg/L)
- PDE inhibitor + adenosine antagonist
- CYP1A2: smoking induces (needs more)
- Levels ↑: ciprofloxacin, macrolides, cimetidine; stopping smoking
Remember Quit the cigarette, check the theophylline.
Why the other options are wrong
- More renal theophylline excretion Excretion is mainly hepatic metabolism.
- Nicotine withdrawal effects Nicotine withdrawal does not usually cause tachyarrhythmia and tremor in this pattern.
- More protein binding Not the mechanism.
- Worsening COPD Symptoms are those of toxicity.
Several men drink illicit spirit and later develop blurred vision and severe metabolic acidosis. Which metabolite damages the optic nerve?
Answer: Formic acid
Methanol is converted by alcohol dehydrogenase to formaldehyde and then formic acid, which causes a high anion gap metabolic acidosis and damages the retina and optic nerve (blindness) and the basal ganglia. Treatment blocks alcohol dehydrogenase with fomepizole (or ethanol), corrects acidosis and uses haemodialysis. Ethylene glycol is converted to glycolic and oxalic acids, causing kidney failure with oxalate crystals.
Toxic alcohols
- Methanol → formic acid: blindness
- Ethylene glycol → oxalate: kidneys
- Both: high anion gap acidosis
- Treat: fomepizole, dialysis
Remember Methanol blinds; ethylene glycol blocks the kidneys.
Exam trap An osmolar gap early suggests a toxic alcohol before acidosis develops.
Why the other options are wrong
- Acetaldehyde From ethanol; causes flushing.
- Oxalic acid Ethylene glycol: kidney damage.
- Glycolic acid Ethylene glycol: acidosis.
- Acetone From isopropyl alcohol; no acidosis.
A patient taking hydralazine develops arthralgia, rash and positive anti-histone antibodies. Which genetic trait increases this risk?
Answer: Slow acetylator
N-acetyltransferase 2 activity is genetically variable. Slow acetylators (about half of South Asians and Europeans) accumulate parent drugs: drug-induced lupus with hydralazine and procainamide (anti-histone antibodies; kidneys and CNS usually spared), peripheral neuropathy with isoniazid (prevented by pyridoxine), and dapsone toxicity. Other drug-induced lupus causes: isoniazid, minocycline, anti-TNF agents.
Acetylator status
- Slow acetylators: drug-induced lupus (hydralazine, procainamide)
- Isoniazid neuropathy (give pyridoxine)
- Drug lupus: anti-histone antibodies
Remember Slow to acetylate, quick to get lupus.
Why the other options are wrong
- Rapid acetylator Clear these drugs faster.
- G6PD deficiency Haemolysis with oxidant drugs.
- Pseudocholinesterase deficiency Prolonged suxamethonium apnoea.
- CYP2D6 ultrarapid metaboliser Codeine toxicity in breastfed infants.
Where this sits in the CPSP syllabus
- Paper 1: General pharmacology, Drug metabolism, CYP450 induction and inhibition, pharmacogenomics
Read next
Drug dose pages
Doses, cautions and practical tips for drugs in this chapter.