Phase I metabolism
• Involves oxidation, reduction, hydrolysis
• Primarily mediated by cytochrome P450 enzymes (CYP450)
• Can activate, inactivate, or generate toxic metabolites
• ↓ in elderly and liver disease, increasing risk of toxicity
Phase II metabolism
• Involves conjugation reactions (e.g. glucuronidation, sulfation, acetylation)
• Converts drugs into more water-soluble compounds for renal or biliary excretion
• Generally preserves drug activity or enhances clearance
Cytochrome P450 Interactions
CYP450 Inducers – ↑ enzyme activity → ↓ drug levels
💡 Mnemonic: CRAP GPS
• Carbamazepine
• Rifampicin
• Alcohol (chronic)
• Phenytoin
• Griseofulvin
• Phenobarbital
• St John's Wort
CYP450 Inhibitors – ↓ enzyme activity → ↑ drug levels
💡 Mnemonic: SICKFACES.COM
• Sodium valproate
• Isoniazid
• Cimetidine
• Ketoconazole
• Fluconazole
• Alcohol (acute)
• Chloramphenicol
• Erythromycin
• Sulfonamides
• Ciprofloxacin
• Omeprazole
• Metronidazole
Pharmacokinetic Concepts
First-pass metabolism
• Drugs absorbed via the GI tract pass through the liver via portal circulation before entering systemic circulation
• Significant hepatic metabolism reduces bioavailability
• Examples: propranolol, verapamil, GTN, morphine
Therapeutic index
• Narrow therapeutic index = small gap between effective and toxic doses
• Requires regular monitoring
• Examples: digoxin, lithium, warfarin, theophylline, phenytoin
Clinical Implications
Drug interactions
• ↑ Risk of toxicity: e.g. erythromycin (inhibitor) + warfarin → ↑ INR → bleeding
• ↓ Efficacy: e.g. enzyme inducers reduce levels of immunosuppressants, anti-epileptics
Oral contraceptive failure
• Due to:
o Enzyme inducers (e.g. rifampicin, carbamazepine)
o Malabsorption (e.g. vomiting, diarrhoea)
Examples of important drug interactions
• Warfarin + antibiotics (e.g. erythromycin, metronidazole) → ↑ INR
• Theophylline + ciprofloxacin → toxicity
• Statins + macrolides (e.g. clarithromycin) → rhabdomyolysis
• SSRIs + tramadol → serotonin syndrome
