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Effects of Ketoconazole on Glucuronidation by UDP-Glucuronosyltransferase Enzymes

Authors' Affiliations: ¹ Committee on Clinical Pharmacology and Pharmacogenomics, ² Department of Medicine, and ³ Cancer Research Center, The University of Chicago, Chicago, Illinois

Requests for reprints: Mark J. Ratain, The University of Chicago, 5841 South Maryland Avenue, MC2115, Chicago, IL 60637. Phone: 773-702-4400; Fax: 773-702-3969; E-mail: mratain{at}medicine.bsd.uchicago.edu.

Purpose: Ketoconazole has been shown to inhibit the glucuronidation of the UGT2B7 substrates zidovudine and lorazepam. Its effect on UGT1A substrates is unclear. A recent study found that coadministration of irinotecan and ketoconazole led to a significant increase in the formation of SN-38 (7-ethyl-10-hydroxycamptothecine), an UGT1A substrate. This study investigates whether ketoconazole contributes to the increase in SN-38 formation by inhibiting SN-38 glucuronidation.

Experimental Design: SN-38 glucuronidation activities were determined by measuring the rate of SN-38 glucuronide (SN-38G) formation using pooled human liver microsomes and cDNA-expressed UGT1A isoforms (1A1, 1A7 and 1A9) in the presence of ketoconazole. Indinavir, a known UGT1A1 inhibitor, was used as a positive control. SN-38G formation was measured by high-performance liquid chromatograph.

Results: Ketoconazole competitively inhibited SN-38 glucuronidation. Among the UGT1A isoforms screened, ketoconazole showed the highest inhibitory effect on UGT1A1 and UGT1A9. The K_i values were 3.3 ± 0.8 µmol/L for UGT1A1 and 31.9 ± 3.3 µmol/L for UGT1A9.

Conclusions: These results show that ketoconazole is a potent UGT1A1 inhibitor, which seems the basis for increased exposure to SN-38 when coadministered with irinotecan.

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