CYP phase-1 drug metabolism overview

Category: drug_metabolism

Overview

Cytochrome P450 superfamily — the dominant phase-1 (oxidative) drug-metabolizing enzymes. Five isoforms handle most clinically used drugs: CYP3A4 (≈50% of marketed drugs — see midazolam, statins, immunosuppressants, opioids, BTK/Bcl-2/JAK inhibitors); CYP2D6 (≈25% — beta-blockers, antidepressants, opioids; highly polymorphic — PM/IM/EM/UM); CYP2C9 (warfarin, NSAIDs, phenytoin); CYP2C19 (omeprazole, clopidogrel — *2/*3 reduced-function alleles); CYP1A2 (caffeine, theophylline, clozapine, smoking-inducible). DDI authoring across the registry maps perpetrator → victim Ki / induction_factor for each of these. Phase-1 metabolism typically increases water solubility for subsequent phase-2 conjugation + phase-3 transport excretion.

Organ Systems

Pathway Steps

  1. lipophilic-drug → oxidized-metabolite — via CYP3A4 / 2D6 / 2C9 / 2C19 / 1A2 / 2B6 / 2E1 etc. — substrate-specific isoform. Cytochrome P450s perform most phase-1 oxidation, with CYP3A4 alone handling ~50% of drugs (gut + liver). They are the hub of pharmacokinetic interactions — inhibitors (ketoconazole, grapefruit, ritonavir) raise substrate levels while inducers (rifampin, carbamazepine, St John’s wort) lower them — and 2D6/2C19 polymorphisms drive poor/ultrarapid-metabolizer phenotypes.

References