Two healthy adult contacts receive identical weight-based isoniazid preventive therapy. One develops symptomatic hepatitis while the other tolerates it well. Genotyping shows they differ at the NAT2 gene locus. The genotype associated with higher risk of isoniazid hepatotoxicity is:

• A Slow acetylator phenotype, leading to accumulation of parent drug
• B Rapid acetylator phenotype, leading to excess hydrazine metabolite formation ✓
• C Slow acetylator phenotype, leading to excess monoacetylhydrazine accumulation
• D Acetylator status does not influence isoniazid hepatotoxicity

Explanation

Isoniazid is inactivated by NAT2-mediated acetylation. Rapid acetylators convert more drug to acetylisoniazid, which hydrolyses to monoacetylhydrazine, the hepatotoxic metabolite normally further detoxified by CYP2E1 and acetylation. Higher flux through this pathway in rapid acetylators increases hepatic injury risk. In contrast, slow acetylators accumulate parent drug and are predisposed to peripheral neuropathy, the opposite association.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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