Two patients receive identical isoniazid preventive therapy. Patient X, phenotypically a slow acetylator via NAT2, develops marked transaminase elevation, while patient Y clears the drug rapidly without hepatic injury. The pharmacokinetic basis of this difference is:

• A Fast acetylators accumulate acetylisoniazid, which is directly hepatotoxic
• B Slow acetylators form more hydrazine metabolite via CYP2E1, increasing hepatotoxic risk ✓
• C Slow acetylators excrete unchanged isoniazid renally, injuring tubular cells
• D NAT2 genotype alters katG expression, changing bacillary killing

Explanation

Isoniazid is inactivated mainly by N-acetyltransferase 2 (NAT2), showing genetic polymorphism. Slow acetylators sustain higher parent drug levels; isoniazid is then oxidised by CYP2E1 to reactive intermediates including hydrazine and acetyl-hydrazine that bind hepatocyte macromolecules, raising the risk of hepatitis. Fast acetylators clear the drug rapidly with less hepatic injury but theoretically need higher doses for efficacy. NAT2 is a host enzyme and does not affect bacterial katG.

Reference: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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