Pharmacogenomics and Precision Medicine
Core concepts
Understand how genetic variation in drug-metabolising enzymes (CYP2D6, CYP2C19, CYP2C9, TPMT, DPYD) and drug targets (e.g., HLA alleles) influences response and toxicity. Know the phenotype categories - poor, intermediate, extensive/normal, ultrarapid metabolisers - and how they alter prodrug activation versus active-drug clearance. Classic examples: CYP2C19 poor metabolisers have reduced clopidogrel activation; CYP2D6 ultrarapid metabolisers may fail on codeine or tamoxifen; HLA-B*57:01 predicts abacavir hypersensitivity; TPMT and DPYD deficiency increase thiopurine and fluoropyrimidine toxicity.
Traps in questions
A frequent trap is assuming a poor metaboliser always needs a higher dose - for a prodrug, poor metabolism means less active drug, so the dose may need to be increased or the drug changed. For an active drug, poor metabolism means more exposure, so the dose may need to be reduced. Watch for questions that ignore ethnicity-specific allele frequencies or that treat pharmacogenomics as deterministic rather than probabilistic.
Worked rule of thumb
Use the prodrug versus active drug rule: identify whether the parent is active. If the parent is a prodrug (clopidogrel, codeine, tamoxifen), reduced enzyme activity lowers effect. If the parent is active (many antidepressants, warfarin), reduced activity raises exposure and toxicity risk. Always pair genotype with clinical context.