Genetic Polymorphisms in Drug Metabolism

Many drug-metabolising enzymes are genetically polymorphic: inherited variation in their genes produces enzymes with reduced, absent, normal, or increased activity. These polymorphisms — classically in CYP2D6, CYP2C19, thiopurine S-methyltransferase, and the N-acetyltransferases — sort individuals into metaboliser phenotypes and are a principal genetic source of variability in drug exposure and response.

Definition

Genetic polymorphism in drug metabolism is heritable variation in the genes encoding drug-metabolising enzymes that produces stable differences in enzyme activity across a population, classifying individuals into metaboliser phenotypes (for example poor, intermediate, extensive, or ultrarapid).

Scope

This topic covers the concept of polymorphic drug metabolism, the metaboliser-phenotype framework, the best-characterised polymorphic enzymes, and the translation of this genetic variation into pharmacogenetic guidance. It is educational and gives no individualised testing or dosing advice.

Core questions

• How does inherited variation in metabolising enzymes produce metaboliser phenotypes?
• Which drug-metabolising enzymes are most clearly polymorphic?
• How do polymorphisms affect exposure to drugs and their active metabolites?
• How is pharmacogenetic variation translated into clinical guidance?

Key concepts

• Metaboliser phenotypes (poor, intermediate, extensive, ultrarapid)
• CYP2D6 and CYP2C19 polymorphism
• Thiopurine S-methyltransferase (TPMT) variation
• N-acetyltransferase acetylator status
• Genotype-to-phenotype translation
• Active-metabolite formation in prodrugs
• Pharmacogenetic dosing guidelines

Mechanisms

Polymorphisms in drug-metabolising genes — including gene deletions, inactivating variants, and gene duplications — change the amount or function of the encoded enzyme, producing a distribution of activity across the population (Evans & Relling, 1999). For an enzyme such as CYP2D6 this yields poor, intermediate, extensive, and ultrarapid metaboliser phenotypes, with corresponding differences in the clearance of its substrates (Zanger & Schwab, 2013). The clinical direction of effect depends on whether metabolism inactivates or activates the drug: poor metabolisers accumulate a parent drug that is normally inactivated, but generate little active product from a prodrug that depends on the same enzyme (Evans & McLeod, 2003). Comparable polymorphisms in CYP2C19, thiopurine S-methyltransferase, and the N-acetyltransferases similarly shape exposure and response. These genotype-phenotype relationships are the basis on which pharmacogenetic working groups derive enzyme-specific recommendations (Swen et al., 2011).

Clinical relevance

Polymorphisms in metabolising enzymes contribute to variability in drug exposure and to the risk of altered response, and are the substrate for pharmacogenetic guidelines. This entry explains the genetic mechanisms and the phenotype framework as reference material; it does not recommend testing or dosing for any individual.

Epidemiology

The frequency of metaboliser phenotypes varies between populations: for example, the proportion of poor or ultrarapid metabolisers at loci such as CYP2D6 and CYP2C19 differs across ancestral groups, which is why allele frequencies are reported by population in pharmacogenetic syntheses (Zanger & Schwab, 2013).

Evidence & guidelines

Professional pharmacogenetics working groups translate genotype into enzyme-specific recommendations; the Dutch Pharmacogenetics Working Group guidelines are a published example of this gene-to-guidance translation (Swen et al., 2011). The underlying genotype-phenotype relationships and their consequences for disposition and response are documented in major reviews (Evans & Relling, 1999; Evans & McLeod, 2003; Zanger & Schwab, 2013; Wilkinson, 2005).

History

Heritable differences in drug metabolism were recognised in the mid-twentieth century through traits such as slow versus fast isoniazid acetylation and the debrisoquine oxidation polymorphism later mapped to CYP2D6. From the 1990s these observations were integrated into pharmacogenomics, which reframed inherited variation in metabolism as a predictable determinant of drug disposition and response (Evans & Relling, 1999; Evans & McLeod, 2003), culminating in formal gene-to-dose guidelines (Swen et al., 2011).

Key figures

• William E. Evans
• Mary V. Relling
• Howard L. McLeod
• Ulrich M. Zanger

Seminal works

• evans-relling-1999
• evans-mcleod-2003
• swen-2011

Frequently asked questions

What is a poor metaboliser?

A poor metaboliser carries gene variants that leave little or no functional activity of a particular drug-metabolising enzyme, so drugs cleared mainly by that enzyme tend to accumulate, while prodrugs that depend on it for activation produce little active drug.

Why does the same polymorphism raise exposure to one drug but lower the effect of another?

It depends on whether the enzyme inactivates or activates the drug. Reduced activity raises levels of a drug that the enzyme normally inactivates, but reduces formation of the active metabolite from a prodrug that the enzyme normally activates.