Skip to main content

Advertisement

SpringerLink
Log in

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

  • Short Communication
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

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 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.

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

References

  1. Jin C, Miners JO, Lillywhite KJ, Mackenzie PI (1993) Complementary deoxyribonucleic acid cloning and expression of a human liver uridine diphosphate-glucuronosyltransferase glucuronidating carboxylic acid-containing drugs. J Pharmacol Exp Ther 264:475–479

    PubMed  CAS  Google Scholar 

  2. Van Hecken A, Verbesselt R, Tjandra-Maga TB, De Schepper PJ (1989) Pharmacokinetic interaction between indomethacin and diflunisal. Eur J Clin Pharmacol 36:507–512

    Article  PubMed  Google Scholar 

  3. Kuehl GE, Lampe JW, Potter JD, Bigler J (2005) Glucuronidation of nonsteroidal anti-inflammatory drugs: identifying the enzymes responsible in human liver microsomes. Drug Metab Dispos 33:1027–1035

    Article  PubMed  CAS  Google Scholar 

  4. Lertora JJ, Rege AB, Greenspan DL, Akula S, George WJ, Hyslop NE Jr, Agrawal KC (1994) Pharmacokinetic interaction between zidovudine and valproic acid in patients infected with human immunodeficiency virus. Clin Pharmacol Ther 56:272–278

    Article  PubMed  CAS  Google Scholar 

  5. Sahai J, Gallicano K, Pakuts A, Cameron DW (1994) Effect of fluconazole on zidovudine pharmacokinetics in patients infected with human immunodeficiency virus. J Infect Dis 169:1103–1107

    PubMed  CAS  Google Scholar 

  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 60:423–433

    Article  PubMed  CAS  Google Scholar 

  7. King C, Tang W, Ngui J, Tephly T, Braun M (2001) Characterization of rat and human UDP-glucuronosyltransferases responsible for the in vitro glucuronidation of diclofenac. Toxicol Sci 61:49–53

    Article  PubMed  CAS  Google Scholar 

  8. Kuehl GE, Bigler J, Potter JD, Lampe JW (2006) Glucuronidation of the aspirin metabolite salicylic acid by expressed UDP-glucuronosyltransferases and human liver microsomes. Drug Metab Dispos 34:199–202

    Article  PubMed  CAS  Google 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 299:998–1006

    PubMed  CAS  Google Scholar 

  10. Mano Y, Usui T, Kamimura H (2006) Identification of human UDP-glucuronosyltransferase responsible for the glucuronidation of niflumic acid in human liver. Pharm Res 23:1502–1508

    Article  PubMed  CAS  Google Scholar 

  11. Miners JO, Mackenzie PI (1991) Drug glucuronidation in humans. Pharmacol Ther 51:347–369

    Article  PubMed  CAS  Google Scholar 

  12. Helleberg L (1981) Clinical Pharmacokinetics of indomethacin. Clin Pharmacokinet 6:245–258

    PubMed  CAS  Google Scholar 

  13. McGurk KA, Remmel RP, Hosagrahara VP, Tosh D, Burchell B (1996) Reactivity of mefenamic acid 1-o-acyl glucuronide with proteins in vitro and ex vivo. Drug Metab Dispos 24:842–849

    PubMed  CAS  Google Scholar 

  14. Lan SJ, Chando TJ, Weliky I, Schreiber EC (1973) Metabolism of niflumic acid-14C: absorption, excretion and biotransformation by human and dog. J Pharmacol Exp Ther 186:323–330

    PubMed  CAS  Google 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 31:1125–1133

    Article  PubMed  CAS  Google Scholar 

  16. Wynalda MA, Wynalda KM, Amore BM, Fagerness PE, Wienkers LC (2003) Characterization of bropirimine O-glucuronidation in human liver microsomes. Xenobiotica 33:999–1011

    Article  PubMed  CAS  Google 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 33:1621–1627

    Article  PubMed  CAS  Google Scholar 

  18. Sim SM, Back DJ, Breckenridge AM (1991) The effect of various drugs on the glucuronidation of zidovudine (azidothymidine; AZT) by human liver microsomes. Br J Clin Pharmacol 32:17–21

    PubMed  CAS  Google Scholar 

  19. Herber R, Magdalou J, Haumont M, Bidault R, van Es H, Siest G. (1992) Glucuronidation of 3′-azido-3′-deoxythymidine in human liver microsomes: enzyme inhibition by drugs and steroid hormones. Biochim Biophys Acta 1139:20–24

    PubMed  CAS  Google Scholar 

  20. Margolis JM, Obach RS (2003) Impact of nonspecific binding to microsomes and phospholipid on the inhibition of cytochrome P4502D6: implications for relating in vitro inhibition data to in vivo drug interactions. Drug Metab Dispos 31:606–611

    Article  PubMed  CAS  Google Scholar 

  21. Mano Y, Usui T, Kamimura H (2005) In vitro inhibitory effects of non-steroidal anti-inflammatory drugs on UDP-glucuronosyltransferase 1A1-catalysed estradiol 3β-glucuronidation in human liver microsomes. Biopharm Drug Dispos 26:35–39

    Article  PubMed  CAS  Google Scholar 

  22. Mano Y, Usui T, Kamimura H (2006) In vitro inhibitory effects of non-steroidal anti-inflammatory drugs on 4-methylumbelliferone glucuronidation in recombinant human UDP-glucuronosyltransferase 1A9-potent inhibition by niflumic acid. Biopharm Drug Dispos 27:1–6

    Article  PubMed  CAS  Google Scholar 

  23. Bauman JN, Goosen TC, Tugnait M, Peterkin V, Hurst SI, Menning LC, Milad M, Court MH, Williams JA (2005) UDP-glucuronosyltransferase 2B7 is the major enzyme responsible for gemcabene glucuronidation in human liver microsomes. Drug Metab Dispos 33:1349–1354

    Article  PubMed  CAS  Google Scholar 

  24. Kaji H, Kume T (2005) Regioselective glucuronidation of denopamine: marked species differences and identification of human udp-glucuronosyltransferase isoform. Drug Metab Dispos 33:403–412

    Article  PubMed  CAS  Google Scholar 

  25. Vietri M, De Santi C, Pietrabissa A, Mosca F, Pacifici GM (2000) Inhibition of human liver phenol sulfotransferase by nonsteroidal anti-inflammatory drugs. Eur J Clin Pharmacol 56:81–87

    Article  PubMed  CAS  Google 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 1707–1792

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Drug Metabolism Research Laboratories, Astellas Pharma Inc., 1-8, Azusawa 1-Chome, Itabashi-ku, Tokyo, 174-8511, Japan

    Yuji Mano, Takashi Usui & Hidetaka Kamimura

Authors
  1. Yuji Mano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takashi Usui
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hidetaka Kamimura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuji Mano.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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 63, 211–216 (2007). https://doi.org/10.1007/s00228-006-0241-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-006-0241-9

Keywords

Search

Navigation