Principles of pharmacology and pharmacokinetics - metabolism, including genetic factors and drug–drug interactions of cytochrome P450 enzymes

Overview

Drug metabolism (predominantly hepatic, via cytochrome P450 enzymes and other pathways) converts drugs to more water-soluble metabolites for excretion - genetic variation in cytochrome P450 enzyme activity (fast, normal, slow, or ultra-rapid metaboliser phenotypes) causes substantial inter-individual variation in drug exposure and response at a standard dose
Foundational to understanding drug interactions and inter-individual dosing variability across essentially all metabolised drugs

CYP450 enzyme induction (e.g. by carbamazepine, rifampicin, St John's Wort) increases metabolic capacity, reducing plasma levels of co-administered drugs metabolised by the same enzyme - onset takes days to weeks as new enzyme protein is synthesised; CYP450 inhibition (e.g. by many antifungals, some antibiotics, grapefruit juice for specific enzymes) reduces metabolic capacity, increasing plasma levels of affected drugs - onset can be rapid, within the timeframe of the inhibiting drug reaching effective concentration
Genetic polymorphism in specific CYP enzymes (e.g. CYP2D6) explains why some patients are "poor metabolisers" (reduced enzyme activity, risking accumulation and toxicity at standard doses) or "ultra-rapid metabolisers" (excessive enzyme activity, risking subtherapeutic effect, or for prodrugs, potentially dangerous excess active metabolite production)

Pharmacogenomic testing is available for specific drug-gene pairs with well-established clinical significance, though not yet routine for most prescribing decisions
Awareness of known enzyme-inducing or enzyme-inhibiting co-medications (and over-the-counter/herbal products, e.g. St John's Wort) should prompt specific interaction screening before adding a new metabolised drug

Dose adjustment or drug avoidance when significant CYP450 interactions are identified, particularly relevant for narrow therapeutic index drugs where even modest level changes matter clinically
Codeine's dependence on CYP2D6 for conversion to active morphine illustrates a specific, clinically important prodrug metabolism scenario - poor metabolisers get inadequate analgesia, while ultra-rapid metabolisers (including some neonates via breastfeeding mothers) risk dangerous morphine excess

Codeine and CYP2D6 polymorphism (poor metaboliser inadequate analgesia vs ultra-rapid metaboliser toxicity risk), St John's Wort as a potent enzyme inducer reducing efficacy of numerous co-medications (including oral contraceptives and some antiretrovirals), grapefruit juice CYP3A4 inhibition interactions
Codeine requires CYP2D6-mediated conversion to its active metabolite morphine to produce analgesic effect - poor metabolisers (a meaningful proportion of the population, varying by ethnicity) get little to no analgesic benefit from codeine regardless of dose, while ultra-rapid metabolisers risk dangerous morphine toxicity, including documented neonatal deaths from breastfeeding mothers who were ultra-rapid metabolisers taking codeine

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