Which of the following best describes the pharmacogenomic basis for the variable response to debrisoquine and other drugs metabolized by the same hepatic enzyme?

• A Polymorphism in CYP2D6 gene causing poor or ultra-rapid metabolizer phenotypes ✓
• B Polymorphism in NAT2 gene causing slow acetylators to have higher plasma drug levels
• C Mutation in TPMT gene causing reduced thiopurine methyltransferase activity
• D Duplication of CYP3A4 gene leading to increased first-pass metabolism

Explanation

Debrisoquine is a prototypic substrate for CYP2D6 polymorphism. Poor metabolizers (PM) carry two non-functional alleles (e.g., CYP2D6*4, *5), accumulate high plasma levels, and experience toxicity; ultra-rapid metabolizers (UM) carry gene duplications and achieve sub-therapeutic levels. CYP2D6 also metabolizes codeine, tamoxifen, metoprolol, and many antidepressants. NAT2 polymorphism affects isoniazid and hydralazine acetylation (option B), and TPMT polymorphism affects thiopurine toxicity (option C).

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.