Key Facts

Drug metabolism is the body's primary mechanism for eliminating lipophilic drugs. The cytochrome P450 system is central to this process. Understanding enzyme induction and inhibition is essential for predicting and managing drug interactions.

Phase I Metabolism

• Cytochrome P450 (CYP) enzymes: superfamily of haem-containing monooxygenases, predominantly in hepatic endoplasmic reticulum
• Most important CYPs: CYP3A4 (~50% of drugs), CYP2D6 (~25%), CYP2C9, CYP2C19, CYP1A2, CYP2E1
• Reactions: oxidation (most common), reduction, hydrolysis, dealkylation
• May convert active drug → inactive metabolite (detoxification) or pro-drug → active metabolite (bioactivation)

Phase II Metabolism

• Conjugation reactions: attach polar group to drug/Phase I metabolite
• Glucuronidation (UGT enzymes): most common Phase II reaction — e.g. morphine → morphine-6-glucuronide (active)
• Acetylation (NAT2): genetically polymorphic — fast/slow acetylators; affects isoniazid, hydralazine, procainamide
• Sulfation, methylation, glutathione conjugation: other Phase II pathways

Enzyme Induction

• Increased synthesis of CYP enzymes → enhanced drug metabolism → reduced plasma levels of substrate drugs
• Takes days to weeks to develop fully (requires new protein synthesis)
• Effect wanes over days to weeks after inducer withdrawn
• Clinical consequence: therapeutic failure of substrate drug

Enzyme Inhibition

• Direct blockade of CYP enzyme active site → reduced metabolism of substrate drugs → increased plasma levels
• Rapid onset (within hours of inhibitor starting)
• Clinical consequence: toxicity of substrate drug

Pathophysiology

• Genetic polymorphisms: CYP2D6, CYP2C19, NAT2, UGT1A1 — affect drug metabolism and response
• Hepatic impairment: reduced CYP activity → impaired Phase I metabolism → drug accumulation
• Age: neonates have immature CYP; elderly have reduced hepatic blood flow and CYP activity
• Gut wall metabolism: CYP3A4 in enterocytes → contributes to first-pass effect (grapefruit juice inhibits gut CYP3A4)

Clinically Important Interactions

• Warfarin + rifampicin (inducer): subtherapeutic INR → thrombosis risk
• Warfarin + erythromycin/clarithromycin (inhibitor): supratherapeutic INR → bleeding risk
• Simvastatin + clarithromycin (CYP3A4 inhibitor): increased statin levels → rhabdomyolysis risk
• Ciclosporin + rifampicin (inducer): subtherapeutic levels → transplant rejection
• Codeine in CYP2D6 ultra-rapid metaboliser: excessive morphine production → respiratory depression, death (especially in children)
• Clopidogrel + omeprazole (CYP2C19 inhibitor): reduced clopidogrel activation → reduced antiplatelet effect

Red Flags

• Starting an enzyme inducer in a patient on warfarin, OCP, ciclosporin, or anticonvulsants → therapeutic failure
• Starting an enzyme inhibitor in a patient on drugs with narrow TI → toxicity risk
• CYP2D6 poor metaboliser on tamoxifen → reduced efficacy (tamoxifen is a pro-drug requiring CYP2D6)
• Grapefruit juice + simvastatin/ciclosporin → toxicity (gut CYP3A4 inhibition)

Clinical Assessment

• Drug interaction check: use BNF interactions checker or electronic prescribing alerts
• Medication review: identify all CYP substrates, inducers, and inhibitors

Therapeutic Drug Monitoring

• TDM for narrow TI drugs: when starting/stopping inducers or inhibitors — e.g. phenytoin, ciclosporin, warfarin (INR), theophylline

Pharmacogenomic Testing

• CYP2D6 genotyping: codeine/tramadol response, tamoxifen efficacy
• CYP2C19 genotyping: clopidogrel response, proton pump inhibitor dosing
• HLA-B*5701: abacavir hypersensitivity (mandatory before prescribing)
• TPMT: azathioprine dosing (not CYP but important pharmacogenomic test)
• DPYD: 5-fluorouracil/capecitabine toxicity

Special Tests

• LFTs: assess hepatic synthetic function — guides dose adjustment
• Child-Pugh score: classifies liver disease severity for drug dosing

Preventing Drug Interactions

• Check BNF drug interactions before prescribing any new drug
• Use electronic prescribing systems: with built-in interaction alerts
• Consider alternative drugs: choose drugs less susceptible to interactions where possible
• Dose adjustment: when co-prescribing inducers/inhibitors, adjust substrate drug dose and monitor

Managing Interactions

• Monitor closely: TDM, INR, clinical response
• Timing: inhibition effects are immediate; induction takes 1–2 weeks to develop and 1–2 weeks to resolve
• Communication: warn patients about interactions, especially with OTC drugs and supplements (St John's wort)

Clinical Pharmacology Input

• Complex polypharmacy with multiple interacting drugs
• Pharmacogenomic testing and interpretation
• TDM interpretation in context of interactions

Referral Criteria

• Clinical pharmacology: complex drug interactions, pharmacogenomic queries
• Specialist team: adjust transplant drugs (ciclosporin, tacrolimus) when starting/stopping interacting drugs

• Drug interactions via CYP450 are a leading cause of adverse drug events
• Preventable with careful prescribing and monitoring
• Pharmacogenomic testing: increasingly available; improves drug safety and efficacy
• Electronic prescribing alerts significantly reduce interaction-related harm
• Knowledge of key inducers/inhibitors is essential for safe prescribing — examined in all UK medical exams

Major CYP Enzymes and Their Drug Substrates

Common Inducers and Inhibitors