TY - JOUR T1 - Comparison of Inhibition Potentials of Drugs against Zidovudine Glucuronidation in Rat Hepatocytes and Liver Microsomes JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 602 LP - 606 DO - 10.1124/dmd.106.014225 VL - 35 IS - 4 AU - Yuji Mano AU - Takashi Usui AU - Hidetaka Kamimura Y1 - 2007/04/01 UR - http://dmd.aspetjournals.org/content/35/4/602.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -