A patient with Gilbert syndrome receiving irinotecan for colorectal cancer develops severe neutropenia and diarrhoea after the first cycle. The toxicity results from impaired conversion of the active SN-38 metabolite to its inactive glucuronide. Which enzyme is deficient?

• A CYP3A4
• B UDP-glucuronosyltransferase 1A1 (UGT1A1) ✓
• C NADPH-cytochrome P450 reductase
• D Epoxide hydrolase

Explanation

UGT1A1 glucuronidates SN-38, the toxic active metabolite of irinotecan, into inactive SN-38G. Reduced UGT1A1 activity, as in Gilbert syndrome (and the homozygous UGT1A1*28 variant), allows SN-38 accumulation and causes dose-limiting myelosuppression and diarrhoea. CYP3A4 handles irinotecan oxidation to inactive metabolites, and epoxide hydrolase acts on arene oxides, not SN-38.

Reference: Katzung Basic and Clinical Pharmacology, 16th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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