Inhibition of UDP-glucuronosyltransferase 2B7-catalyzed morphine glucuronidation by ketoconazole: Dual mechanisms involving a novel noncompetitive mode

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

研究成果: ジャーナルへの寄稿記事

53 引用 (Scopus)

抄録

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 that by 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-type mechanism. Codeine potentiated inhibition of morphine glucuronidation by ketoconazole. In contrast, 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 noncompetitive inhibition.

元の言語英語
ページ(範囲)1277-1282
ページ数6
ジャーナルDrug Metabolism and Disposition
34
発行部数8
DOI
出版物ステータス出版済み - 7 24 2006

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Glucuronosyltransferase
Ketoconazole
Morphine
Liver Microsomes
Nifedipine
Liver
Sulfaphenazole
Codeine
Cimetidine
Erythromycin
Cytochromes
NADP
Metabolism
Testosterone
Kinetics

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Toxicology

これを引用

Inhibition of UDP-glucuronosyltransferase 2B7-catalyzed morphine glucuronidation by ketoconazole : Dual mechanisms involving a novel noncompetitive mode. / Takeda, Shuso; Kitajima, Yurie; Ishii, Yuji; Nishimura, Yoshio; Mackenzie, Peter I.; Oguri, Kazuta; Yamada, Hideyuki.

:: Drug Metabolism and Disposition, 巻 34, 番号 8, 24.07.2006, p. 1277-1282.

研究成果: ジャーナルへの寄稿記事

Takeda, Shuso ; Kitajima, Yurie ; Ishii, Yuji ; Nishimura, Yoshio ; Mackenzie, Peter I. ; Oguri, Kazuta ; Yamada, Hideyuki. / Inhibition of UDP-glucuronosyltransferase 2B7-catalyzed morphine glucuronidation by ketoconazole : Dual mechanisms involving a novel noncompetitive mode. :: Drug Metabolism and Disposition. 2006 ; 巻 34, 番号 8. pp. 1277-1282.
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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 that by 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-type mechanism. Codeine potentiated inhibition of morphine glucuronidation by ketoconazole. In contrast, 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 noncompetitive inhibition.",
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