Genetic Variation in Drug Metabolism

Genetic variation in drug-metabolising enzymes — the subject of pharmacogenetics — explains much of why people differ in how they handle the same drug. Inherited polymorphisms in genes such as CYP2D6, CYP2C19, CYP2C9, TPMT, and UGT1A1 can make individuals poor, intermediate, extensive, or ultrarapid metabolisers, altering the concentration of active drug and the chance of insufficient effect or toxicity. These differences are heritable, vary between populations, and form a chemical-genetic basis for individualised pharmacology.

Definition

Genetic variation in drug metabolism refers to inherited differences (polymorphisms) in the genes encoding drug-metabolising enzymes that change enzyme activity, classifying individuals into metaboliser phenotypes and contributing to variability in drug exposure and response.

Scope

The topic covers how inherited variation in metabolising-enzyme genes produces distinct metaboliser phenotypes, the major polymorphic enzymes involved, and how this variation is described and applied through pharmacogenetics. It treats genetic variation as a chemical, genetic, and pharmacological topic within drug metabolism; it is not clinical dosing guidance.

Core questions

• How do inherited polymorphisms change drug-metabolising enzyme activity?
• What do the metaboliser phenotypes (poor, intermediate, extensive, ultrarapid) mean?
• Which enzymes are most clinically important polymorphic targets?
• Why do metaboliser allele frequencies differ between populations?
• How does pharmacogenetics translate this variation into knowledge for drug use?

Key concepts

• Pharmacogenetics
• Genetic polymorphism
• Metaboliser phenotypes (PM, IM, EM, UM)
• Star (*) allele nomenclature
• Polymorphic enzymes (CYP2D6, CYP2C19, CYP2C9, TPMT, UGT1A1)
• Gene copy number and duplication
• Genotype-phenotype correlation
• Population allele-frequency differences

Mechanisms

Inherited sequence differences — single-nucleotide variants, small insertions or deletions, gene deletions, and gene duplications — alter the amount or catalytic activity of a metabolising enzyme. Loss-of-function variants reduce or abolish activity, producing intermediate or poor metabolisers in whom a substrate drug accumulates, whereas gene duplication can produce ultrarapid metabolisers who clear a drug faster than usual; for prodrugs that require activation, the relationship is reversed. Variant alleles are catalogued with star (*) nomenclature, and combining the two inherited alleles predicts a metaboliser phenotype. Because these alleles arose and spread differently across human populations, their frequencies — and therefore the typical metaboliser distributions — differ between ancestry groups.

Clinical relevance

Genetic variation in metabolism helps explain why a standard exposure to a drug can produce too little effect in rapid metabolisers or excessive exposure and adverse effects in poor metabolisers, and it is the basis for pharmacogenetic testing and dosing frameworks. This entry explains the underlying genetics and chemistry as reference knowledge; it describes how variation influences drug handling and is not a source of individualised testing or dosing recommendations.

Epidemiology

Allele frequencies of the major polymorphic metabolising enzymes vary substantially between populations: large-scale sequencing surveys show that the distribution of cytochrome P450 variant alleles, and hence of poor- and ultrarapid-metaboliser phenotypes, differs markedly across world regions, which is part of why metaboliser status cannot be assumed from a single global figure.

Evidence & guidelines

Evidence comes from genotype-phenotype association studies, population sequencing surveys, and clinical pharmacokinetic studies, synthesised into pharmacogenetic resources and dosing frameworks such as those of the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group. Those guidelines translate genotype into prescribing guidance for clinicians; the topic entry here is an educational overview rather than a protocol.

History

Pharmacogenetics emerged in the 1950s from observations of inherited differences in drug handling, such as variable isoniazid acetylation and prolonged response to succinylcholine, leading to the concept that 'inborn errors' of metabolism shape drug response. The discovery of the debrisoquine/sparteine (CYP2D6) polymorphism in the late 1970s and the subsequent molecular characterisation of polymorphic enzyme genes turned the field into a defined chemical-genetic science, later broadened into genome-wide pharmacogenomics.

Key figures

• William E. Evans
• Mary V. Relling
• Richard M. Weinshilboum
• Magnus Ingelman-Sundberg

Seminal works

• evans-relling-1999
• wang-2011

Frequently asked questions

What is a 'poor metaboliser'?

A poor metaboliser inherits two reduced- or loss-of-function alleles of a metabolising enzyme and therefore breaks down its substrate drugs slowly, which tends to raise drug levels; for prodrugs that need activation, the same status can instead reduce the active-drug level.

Why does metaboliser status differ between populations?

The variant alleles that determine enzyme activity arose and spread differently during human history, so their frequencies — and the resulting metaboliser distributions — vary between ancestry groups, as shown by population-scale sequencing surveys.