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Drug Metabolism and Disposition Fast Forward
First published on January 31, 2007; DOI: 10.1124/dmd.106.014225

0090-9556/07/3504-602-606$20.00
DMD 35:602-606, 2007

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Comparison of Inhibition Potentials of Drugs against Zidovudine Glucuronidation in Rat Hepatocytes and Liver Microsomes

Yuji Mano, Takashi Usui, and Hidetaka Kamimura

Drug Metabolism Research Laboratories, Astellas Pharma Inc., Tokyo, Japan.

Hepatocytes and liver microsomes are considered to be useful for investigating drug metabolism catalyzed mainly via glucuronidation. However, there have been few reports comparing the glucuronidation inhibition potentials of drug in hepatocytes to those in liver microsomes. 3'-Azido-3'-deoxythymidine (AZT, zidovudine) glucuronidation (AZTG) is the major metabolic pathway for AZT. In this study, the inhibition potentials of drugs against UDP-glucuronosyltransferase (UGT)-catalyzed AZTG in the hepatocytes and liver microsomes of rats are compared. The AZTG inhibition potentials of diclofenac, diflunisal, fluconazole, indomethacin, ketoprofen, mefenamic acid, naproxen, niflumic acid, and valproic acid in liver microsomes and hepatocytes were investigated using liquid chromatography with tandem mass spectrometry. Diflunisal (inhibition type: noncompetitive) inhibited AZTG most potently in rat liver microsomes (RLMs) with an IC50 value of 34 µM. The IC50 values of diclofenac, fluconazole, indomethacin, ketoprofen, mefenamic acid, naproxen, niflumic acid, and valproic acid against AZTG in RLMs ranged from 34 to 1791 µM. Diclofenac, diflunisal, indomethacin, ketoprofen, naproxen, and valproic acid inhibited AZTG in hepatocytes with IC50 values of 58, 37, 88, 361, 486, and 281 µM, respectively. These values were similar to those obtained in RLMs. In conclusion, the AZT glucuronidation inhibition potentials of drugs in the hepatocytes and liver microsomes of rats were found to be similar, and liver microsomes can be useful for evaluating UGT isozyme inhibition potentials.

Address correspondence to: Dr. Yuji Mano, Drug Metabolism Research Laboratories, Astellas Pharma Inc., 1-8, Azusawa 1-Chome, Itabashi-ku, Tokyo, 174-8511, Japan. E-mail: yuuji.mano{at}jp.astellas.com




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