Effects of ketoconazole on glucuronidation by UDP-glucuronosyltransferase enzymes.
OBJECTIVE
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.


METHODS
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.
Yong
Wei Peng
WP
Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, IL 60637, USA.
Ramirez
Jacqueline
J
Innocenti
Federico
F
Ratain
Mark J
MJ
D002166:Camptothecin / Q000031:analogs & derivatives / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005965:Glucuronates / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019469:Indinavir / Q000494:pharmacology; D000077146:Irinotecan; D007527:Isoenzymes / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology*; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D013379:Substrate Specificity; D000099148:UGT1A1 Enzyme
D002166:Camptothecin; D005965:Glucuronates; D014453:Glucuronosyltransferase; D019469:Indinavir; D000077146:Irinotecan; D007527:Isoenzymes; D007654:Ketoconazole; D000099148:UGT1A1 Enzyme; C114685:7-ethyl-10-hydroxycamptothecin beta-glucuronide