Principles of Drug Metabolism and Interactions

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