Which statement best describes the pharmacogenomic basis for variable response to metoprolol in different patients?

• A VKORC1 polymorphism determines metoprolol dose requirements
• B CYP3A4 induction increases metoprolol plasma levels in extensive metabolizers
• C N-acetyltransferase polymorphism causes variable metoprolol effects in different ethnic groups
• D CYP2D6 polymorphism; poor metabolizers have higher plasma levels and exaggerated beta-blockade ✓

Explanation

Metoprolol is a substrate of CYP2D6. Poor metabolizers (homozygous CYP2D6*4 or similar loss-of-function alleles) have significantly higher plasma concentrations, leading to excessive bradycardia, fatigue, and risk of heart block. Extensive metabolizers clear the drug rapidly. VKORC1 is relevant to warfarin; CYP3A4 induction would lower, not increase, metoprolol levels; N-acetyltransferase is relevant to drugs like isoniazid and hydralazine.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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