Inhibitory potential of nonsteroidal anti-inflammatory drugs on UDP-glucuronosyltransferase 2B7 in human liver microsomes
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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).
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.
Mefenamic acid inhibited AZTG most potently, with an IC50 value of 0.3 μM, and its inhibition type was not competitive. The IC50 values for diclofenac, diflunisal, indomethacin, ketoprofen, naproxen, and niflumic acid against AZTG were 6.8, 178, 51, 40, 23, and 83 μM, respectively, while those for acetaminophen and salicylic acid were >100 μM. The IC50 values for NSAIDs against AZTG in recombinant human UGT2B7 were similar to those obtained in HLM.
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.
KeywordsAZT UGT2B7 Inhibition NSAIDs Human
- 6.Bowalgaha K, Elliot DJ, Mackenzie PI, Knights KM, Swedmark S, Miners JO (2005) S-Naproxen and desmethylnaproxen glucuronidation by human liver microsomes and recombinant human UDP-glucuronosyltransferases (UGT): role of UGT2B7 in the elimination of naproxen. Br J Clin Pharmacol 60:423–433PubMedCrossRefGoogle Scholar
- 9.Court MH, Duan SX, von Moltke LL, Greenblatt DJ, Patten CJ, Miners JO, Mackenzie PI (2001) Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDP-glucuronosyltransferase isoforms. J Pharmacol Exp Ther 299:998–1006PubMedGoogle Scholar
- 15.Court MH, Krishnaswamy S, Hao Q, Duan SX, Patten CJ, Von Moltke LL, Greenblatt DJ (2003) Evaluation of 3′-azido-3′-deoxythymidine, morphine, and codeine as probe substrates for UDP-glucuronosyltransferase 2B7 (UGT2B7) in human liver microsomes: specificity and influence of the UGT2B7*2 polymorphism. Drug Metab Dispos 31:1125–1133PubMedCrossRefGoogle Scholar
- 17.Engtrakul JJ, Foti RS, Strelevitz TJ, Fisher MB (2005) Altered AZT (3′-azido-3′-deoxythymidine) glucuronidation kinetics in liver microsomes as an explanation for underprediction of in vivo clearance: comparison to hepatocytes and effect of incubation environment. Drug Metab Dispos 33:1621–1627PubMedCrossRefGoogle Scholar
- 26.Benet LZ, Oie S, Schwartz JB (1996) Design and optimization of dosage regimens: pharmacokinetic data. In: hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG (eds) The pharmacological basis of therapeutics, 9th edn. McGraw-Hill, New York, pp 1707–1792Google Scholar