Effects of ketoconazole on glucuronidation by UDP-glucuronosyltransferase enzymes.

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Yong WP, Ramirez J, Innocenti F, Ratain MJ

Effects of ketoconazole on glucuronidation by UDP-glucuronosyltransferase enzymes.

Clin Cancer Res. 2005 Sep 15;11(18):6699-704. doi: 10.1158/1078-0432.CCR-05-0703.

PubMed ID

16166450 [ View in PubMed

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Abstract

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 micromol/L for UGT1A1 and 31.9 +/- 3.3 micromol/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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Indinavir	UDP-glucuronosyltransferase 1-1	Protein	Humans	Unknown	Inhibitor	Details
Ketoconazole	UDP-glucuronosyltransferase 1-1	Protein	Humans	Unknown	Inhibitor	Details
Ketoconazole	UDP-glucuronosyltransferase 1-7	Protein	Humans	Unknown	Inhibitor	Details
Ketoconazole	UDP-glucuronosyltransferase 2B7	Protein	Humans	Unknown	Inhibitor	Details