Inhibitory potential of nonsteroidal anti-inflammatory drugs on UDP-glucuronosyltransferase 2B7 in human liver microsomes.

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Mano Y, Usui T, Kamimura H

Inhibitory potential of nonsteroidal anti-inflammatory drugs on UDP-glucuronosyltransferase 2B7 in human liver microsomes.

Eur J Clin Pharmacol. 2007 Feb;63(2):211-6. Epub 2007 Jan 3.

PubMed ID

17200831 [ View in PubMed

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Abstract

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. CONCLUSION: 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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Indomethacin	UDP-glucuronosyltransferase 2B7	Protein	Humans	Unknown	Substrate Inhibitor	Details