Comparison of inhibition potentials of drugs against zidovudine glucuronidation in rat hepatocytes and liver microsomes.
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 IC(50) value of 34 microM. The IC(50) values of diclofenac, fluconazole, indomethacin, ketoprofen, mefenamic acid, naproxen, niflumic acid, and valproic acid against AZTG in RLMs ranged from 34 to 1791 microM. Diclofenac, diflunisal, indomethacin, ketoprofen, naproxen, and valproic acid inhibited AZTG in hepatocytes with IC(50) values of 58, 37, 88, 361, 486, and 281 microM, 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.
Mano
Yuji
Y
Drug Metabolism Research Laboratories, Astellas Pharma Inc., 1-8, Azusawa 1-Chome, Itabashi-ku, Tokyo, 174-8511, Japan. yuuji.mano@jp.astellas.com
Usui
Takashi
T
Kamimura
Hidetaka
H
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D015394:Molecular Structure; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism; D015215:Zidovudine / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000927:Anticonvulsants; D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D020719:Glucuronides; D018894:Reverse Transcriptase Inhibitors; D014535:Uridine Diphosphate Glucuronic Acid; D015215:Zidovudine; D014453:Glucuronosyltransferase