Inhibitory potential of nonsteroidal anti-inflammatory drugs on UDP-glucuronosyltransferase 2B7 in human liver microsomes.
OBJECTIVE
A number of nonsteroidal anti-inflammatory drugs (NSAIDs) are subject to glucuronidation in humans, and UDP-glucuronosyltransferase (UGT) 2B7 is involved in the glucuronidation of many NSAIDs. The objective of this study was to identify a NSAID with potent inhibitory potential against UGT2B7 using liquid chromatography with tandem mass spectrometry (LC-MS/MS).


METHODS
A rapid screening method for detecting the inhibitory potential of various drugs against UGT2B7 was established using a LC-MS/MS system. The effects of nine NSAIDs (acetaminophen, diclofenac, diflunisal, indomethacin, ketoprofen, mefenamic acid, naproxen, niflumic acid, and salicylic acid) against UGT2B7-catalyzed 3'-azido-3'-deoxythymidine glucuronidation (AZTG) were investigated in human liver microsomes (HLM) and recombinant human UGT2B7.


RESULTS
Mefenamic acid inhibited AZTG most potently, with an IC(50) value of 0.3 microM, and its inhibition type was not competitive. The IC(50) values for diclofenac, diflunisal, indomethacin, ketoprofen, naproxen, and niflumic acid against AZTG were 6.8, 178, 51, 40, 23, and 83 microM, respectively, while those for acetaminophen and salicylic acid were >100 microM. The IC(50) values for NSAIDs against AZTG in recombinant human UGT2B7 were similar to those obtained in HLM.


CONCLUSIONS
The method established in this study is useful for identifying drugs with inhibitory potential against human UGT2B7. Among the nine NSAIDs investigated, mefenamic acid had the strongest inhibitory effect on UGT2B7-catalyzed AZTG in HLM. Thus, caution might be exercised when mefenamic acid is coadministered with drugs possessing UGT2B7 as a main elimination pathway.
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
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008528:Mefenamic Acid / Q000008:administration & dosage / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D015215:Zidovudine / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D020719:Glucuronides; D018894:Reverse Transcriptase Inhibitors; D008528:Mefenamic Acid; D015215:Zidovudine; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase