Microbial Metabolism of Rofecoxib, A Selective COX-2 Inhibitor

Authors

  • Khaled Orabi Kuwait University, Safat

DOI:

https://doi.org/10.6000/1927-3037.2012.01.04.3

Keywords:

Rofecoxib, Cunninghamella echinulata var. echinulata, COX-2 inhibitor, 3'-hydroxyrofecoxib, 4'-hydroxyrofecoxib

Abstract

Microbial transformation studies of rofecoxib (1), a potent selective cyclooxygenase-2 inhibitor, using sixty microorganisms, mainly fungi and actinomycetes, have revealed that it was metabolized by three microorganisms. Using a standard two-stage screening technique, Cunninghamella echinulata var. echinulata ATCC 9244, Mucor griseocyanus ATCC 1207b, and Rhizopus oryzae ATCC 34121 showed two common more polar metabolites 2 and 3. Moreover, it was apparent that Cunninghamella echinulata var. echinulata was the most efficient microorganism to almost completely metabolize 1, and hence, was selected for preparative scale fermentation. These metabolites were characterized on the basis of their spectral data as 4'-hydroxyrofecoxib (2) and 3'-hydroxyrofecoxib (3).

Author Biography

Khaled Orabi, Kuwait University, Safat

Department of Pharmaceutical Chemistry

References


[1] Dennis EA. Phospholipase A2 in eicosanoid generation. Am J Respir Crit Care Med 2000; 161: S32-35.
[2] Marnett LJ, Rowlinson SW, Goodwin DC, Kalgutkar AS, Lanzo CA. Arachidonic acid oxygenation by COX-1 and COX-2. Mechanisms of catalysis and inhibition. J Biol Chem 1999; 13: 22903-6. http://dx.doi.org/10.1074/jbc.274.33.22903
[3] Xie W, Chipman JG, Robertson DL, Erikson RL, Simmons DL. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci USA 1991; 88: 2692-6. http://dx.doi.org/10.1073/pnas.88.7.2692
[4] Vane JR, Botting RM. Overview-mechanisms of action of anti-inflammatory drugs. In: Vane JR, Botting J, Botting R, Ed.Improved non-steroidal anti-inflammatory drugs. 1st ed. London: Kluwer Academic Publishers and William Harvey Press 1996; pp. 1-27. http://dx.doi.org/10.1007/978-94-010-9029-2_1
[5] Donnelly MT, Hawkey CJ. COX-II inhibitors-a new generation of safer NSAIDs? Aliment Pharmacol Ther 1997;11: 227-36. http://dx.doi.org/10.1046/j.1365-2036.1997.154330000.x
[6] Jouzeau J-Y, Terlain B, Abid A, Nedelec E, Netter P. Cyclo-oxygenase isoenzymes. How recent findings affect thinking about nonsteroidal anti-inflammatory drugs. Drugs 1997; 53: 563-82. http://dx.doi.org/10.2165/00003495-199753040-00003
[7] Walker MC, Kurumbail RG, Kiefer JR, Moreland KT, Koboldt CM, Isakson PC. A three-step kinetic mechanism for selective inhibition of cyclo-oxygenase-2 by diarylheterocyclic inhibitors. Biochem J 2001; 357: 709-18. http://dx.doi.org/10.1042/0264-6021:3570709
[8] Ehrich EW, Dallob A, De Lepeleire I, Van Hecken A, Riendeau D, Yuan W. Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model. Clin Pharmacol Ther 1999; 65: 336-47. http://dx.doi.org/10.1016/S0009-9236(99)70113-X
[9] Neal MD, Fakhreddin J. COX-2 selective inhibitors cardiac toxicity: getting to the heart of the matter. J Pharm Pharmaceut Sci 2004; 7: 332-6.
[10] Orabi KY. Microbial models of mammalian metabolism. Sampangines. In: Atta-Ur-Rahman, editor. Studies in natural products chemistry-Bioactive natural products, Part D. New York: Elsevier 2000; pp. 3-49.
[11] Rosazza JP, Smith RV. Microbial models of mammalian metabolism. Appl Microbiol 1979; 25: 169-208. http://dx.doi.org/10.1016/S0065-2164(08)70150-3
[12] Orabi KY, Li E, Clark AM, Hufford CD. Microbial transformation of sampangine. J Nat Prod 1999; 62: 988-92. http://dx.doi.org/10.1021/np980457a
[13] Rosazza JP, Smith RV. Microbial models of mammalian metabolism. J Pharm Sci 1975; 64: 1733-59.
[14] Halpin RA, Geer LA, Zhang KE, et al. The absorption, distribution, metabolism and excretion of rofecoxib, a potent and selective COX-2 inhibitor, in rats and dogs. Drug Metab Dispos 2000; 28: 1244-54.
[15] Halpin R, Porras A, Geer L, et al. The disposition and metabolism of rofecoxib, a potent and selective cyclooxygenase-2 inhibitor, in human subjects. Drug Metab Dispos 2002; 30: 684-93. http://dx.doi.org/10.1124/dmd.30.6.684
[16] Abdul Rahim M, Praveen PN, Knaus EE. Isomeric acetoxy analogues of rofecoxib: a novel class of highly potent and selective cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 2002; 12: 2753-56. http://dx.doi.org/10.1016/S0960-894X(02)00537-1

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Published

2013-01-06

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