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First published on May 5, 2006; DOI: 10.1124/dmd.106.009738

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Received for publication February 9, 2006.
Revised April 25, 2006.
Accepted for publication April 25, 2006.

INHIBITION OF UDP-GLUCURONOSYLTRANSFERASE 2B7-CATALYZED MORPHINE GLUCURONIDATION BY KETOCONAZOLE: DUAL MECHANISMS INVOLVING A NOVEL NON-COMPETITIVE MODE

Shuso Takeda 1, Yurie Kitajima 1, Yuji Ishii 1, Yoshio Nishimura 1, Peter I. Mackenzie 2, Kazuta Oguri 3, Hideyuki Yamada 1*

1 Kyushu University 2 Flinders Medical Centre and Flinders University 3 Kyushu University of Health and Welfare

* Address correspondence to: E-mail: yamada{at}xenoba.phar.kyushu-u.ac.jp

Abstract

Glucuronidation of morphine in humans is predominantly catalyzed by UDP-glucuronosyltransferase 2B7 (UGT2B7). Since our recent research suggested that cytochrome P450s (P450s) interact with UGT2B7 to affect its function [Takeda S. et al. (2005) Mol Pharmacol 67:665-672], P450 inhibitors are expected to modulate UGT2B7-catalyzed activity. To address this issue, we investigated the effects of P450 inhibitors (cimetidine, sulfaphenazole, erythromycin, nifedipine, and ketoconazole) on the UGT2B7-catalyzed formation of morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G). Among the inhibitors tested, ketoconazole was the most potent inhibitor of both M-3-G and M-6-G formation by human liver microsomes. The others were less effective except that nifedipine exhibited an inhibitory effect on M-6-G formation comparable to ketoconazole. Neither addition of NADPH nor solubilization of liver microsomes affected the ability of ketoconazole to inhibit morphine glucuronidation. In addition, ketoconazole had an ability to inhibit morphine UGT activity of recombinant UGT2B7 freed from P450. Kinetic analysis suggested that the ketoconazole-produced inhibition of morphine glucuronidation involves a mixed-mechanism. Codeine potentiated inhibition of morphine glucuronidation by ketoconazole. On the contrary, addition of another substrate, testosterone, showed no or a minor effect on ketoconazole-produced inhibition of morphine UGT. These results suggest that 1) metabolism of ketoconazole by P450 is not required for inhibition of UGT2B7-catalyzed morphine glucuronidation; and 2) this drug exerts its inhibitory effect on morphine UGT by novel mechanisms involving competitive and non-competitive inhibition.


Key words: CYP3A, cytochrome P450, enzyme inhibitors, enzyme kinetics, glucuronidation, protein-protein interactions, UDP glucuronyltransferases


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