Studies on the metabolism of the novel, selective cyclooxygenase-2 inhibitor indomethacin phenethylamide in rat, mouse, and human liver microsomes: Identification of active metabolites

Drug Metabolism and Disposition

Volumn 32, Issue 1, 2004, Pages 113-122

  Remmel, Rory P ^a,b   Crews, Brenda C ^a   Kozak, Kevin R ^a   Algutkar, Amit S ^a,c   Marnett, Lawrence J ^a  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF MINNESOTA   (United States)

^c PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1' HYDROXYINDOMETACIN PHENETHYLAMIDE; 2' HYDROXYINDOMETACIN PHENETHYLAMIDE; 2' OXOINDOMETACIN PHENETHYLAMIDE; CELECOXIB; CYCLOOXYGENASE 1; CYCLOOXYGENASE 2; CYCLOOXYGENASE 2 INHIBITOR; CYTOCHROME P450 3A4; CYTOCHROME P450 3A4 INHIBITOR; DRUG METABOLITE; INDOMETACIN; INDOMETACIN DERIVATIVE; INDOMETACIN PHENETHYLAMIDE; KETOCONAZOLE; LM 4106; LM 4108; LM 5105; LUMIRACOXIB; O NOR 2' HYDROXYINDOMETACIN PHENETHYLAMIDE; TROLEANDOMYCIN; UNCLASSIFIED DRUG; VALDECOXIB;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BILE; CATALYSIS; CONTROLLED STUDY; DEMETHYLATION; DRUG METABOLISM; ENZYME INHIBITION; ENZYME METABOLISM; ENZYME SPECIFICITY; HALF LIFE TIME; HUMAN; IC 50; INCUBATION TIME; LIQUID CHROMATOGRAPHY; LIVER MICROSOME; MASS SPECTROMETRY; MOLECULAR CLONING; MOUSE; NONHUMAN; OXIDATION; OXIDATION KINETICS; PRIORITY JOURNAL; RAT; SPECIES IDENTIFICATION; TANDEM MASS SPECTROMETRY; TISSUE DISTRIBUTION;

ANIMALS; BILE; BIOTRANSFORMATION; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; CYCLOOXYGENASE 2; CYCLOOXYGENASE 2 INHIBITORS; CYCLOOXYGENASE INHIBITORS; CYTOCHROME P-450 ENZYME SYSTEM; HUMANS; INDOMETHACIN; INJECTIONS, INTRAVENOUS; ISOENZYMES; MASS SPECTROMETRY; MEMBRANE PROTEINS; MICE; MICROSOMES, LIVER; PROSTAGLANDIN-ENDOPEROXIDE SYNTHASES; RATS; RECOMBINANT PROTEINS; SPECIES SPECIFICITY;

ANIMALIA;

EID: 1642457365     PISSN: 00909556     EISSN: None     Source Type: Journal    
DOI: 10.1124/dmd.32.1.113     Document Type: Article

References (30)

1. Brune K (2002) Next generation of everyday analgesics. Am J Ther 9:215-223.
2. Daniel TO, Liu H, Morrow JD, Crews BC, and Marnett LJ (1999) Thromboxane A2 is a mediator of cyclooxygenase-2-dependent endothelial migration and angiogenesis. Cancer Res 59:4574-4577.
3. de Groot MJ, Bijloo GJ, Martens BJ, van Acker FA, and Vermeulen NP (1997) A refined substrate model for human cytochrome P450 2D6. Chem Res Toxicol 10:41-48.
4. Gottesdiener K, Schnitzer T, Fisher C, Bockow B, Markenson J, Ko A, DeTora L, Curtis S, Geissler L, and Gertz BJ (2002) Results of a randomized, dose-ranging trial of etoricoxib in patients with osteoarthritis. Rheumatology (Oxf) 41:1052-1061.
5. Guengerich FP (1994) Analysis and characterization of enzymes, in Principles and Methods of Toxicology (Hayes WA ed) pp 1267-1269, Raven Press, New York,
6. Herschman HR (1996) Prostaglandin synthase 2. Biochim Biophys Acta 1299:125-140.
7. Jones BC, Hawksworth G, Horne VA, Newlands A, Morsman J, Tute MS, and Smith DA (1996a) Putative active site template model for cytochrome P4502C9 (tolbutamide hydroxylase). Drug Metab Dispos 24:260-266.
8. Jones JP, He M, Trager WF, and Rettie AE (1996b) Three-dimensional quantitative structure-activity relationship for inhibitors of cytochrome P4502C9. Drug Metab Dispos 24:1-6.
9. Kalgutkar AS, Crews BC, Rowlinson SW, Garner C, Seibert K, and Marnett LJ (1998) Aspirin-like molecules that covalently inactivate cyclooxygenase-2. Science (Wash DC) 280:1268-1270.
10. Kalgutkar AS, Crews BC, Rowlinson SW, Marnett AB, Kozak KR, Remmel RP, and Marnett LJ (2000a) Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors. Proc Natl Acad Sci USA 97:925-930.
11. Kalgutkar AS, Mamett AB, Crews BC, Remmel RP, and Marnett LJ (2000b) Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors. J Med Chem 43:2860-2870.
12. Kalgutkar AS, Rowlinson SW, Crews BC, and Marnett LJ (2002) Amide derivatives of meclofenamic acid as selective cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 12:521-524.
13. Kozak KR, Prusakiewicz JJ, Rowlinson SW, and Marnett LJ (2002) Enantiospecific, selective cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 12:1315-1318.
14. Lewis DF, Dickins M, Weaver RJ, Eddershaw PJ, Goldfarb PS, and Tarbit MH (1998) Molecular modelling of human CYP2C subfamily enzymes CYP2C9 and CYP2C19: rationalization of substrate specificity and site-directed mutagenesis experiments in the CYP2C subfamily. Xenobiotica 28:235-268.
15. Lewis DF, Eddershaw PJ, Goldfarb PS, and Tarbit MH (1997) Molecular modelling of cytochrome P4502D6 (CYP2D6) based on an alignment with CYP102: structural studies on specific CYP2D6 substrate metabolism. Xenobiotica 27:319-339.
16. Marnett LJ and Kalgutkar AS (1999) Cyclooxygenase 2 inhibitors: discovery, selectivity and the future. Trends Pharmacol Sci 20:465-469.
17. Marnett LJ, Rowlinson SW, Goodwin DC, Kalgutkar AS, and Lanzo CA (1999) Arachidonic acid oxygenation by COX-1 and COX-2. Mechanisms of catalysis and inhibition. J Biol Chem 274:22903-22906.
18. Masferrer JL, Zweifel BS, Manning PT, Hauser SD, Leahy KM, Smith WG, Isakson PC, and Seibert K (1994) Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and non-ulcerogenic. Proc Natl Acad Sci USA 91:3228-3232.
19. McKenna F, Arguelles L, Burke T, Lefkowith J, and Geis GS (2002) Upper gastrointestinal tolerability of celecoxib compared with diclofenac in the treatment of osteoarthritis and rheumatoid arthritis. Clin Exp Rheumatol 20:35-43.
20. Nakajima M, Inoue T, Shimada N, Tokudome S, Yamamoto T, and Kuroiwa Y (1998) Cytochrome P450 2C9 catalyzes indomethacin O-demethylation in human liver microsomes. Drug Metab Dispos 26:261-266.
21. Omura T and Sato R (1964) The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. J Biol Chem 239:2370-2378.
22. Ormrod D, Wellington K, and Wagstaff AJ (2002) Valdecoxib. Drugs 62:2059-2071.
23. Poli-Scaife S, Attias R, Dansette PM, and Mansuy D (1997) The substrate binding site of human liver cytochrome P450 2C9: an NMR study. Biochemistry 36:12672-12682.
24. Remmel RP, Crews BC, Kozak KR, Kalgutkar AS, and Mamett LJ (2000) Pharmacokinetics and metabolism of indomethacin-phenethyl amide (LM-4108), a selective COX-2 inhibitor, in rats and mice (Abstract). Drug Metab Rev 32:94.
25. Seibert K, Zhang Y, Leahy K, Hauser S, Masferrer J, Perkins W, Lee L, and Isakson P (1994) Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA 91:12013-12017.
26. Smith WL and Langenbach R (2001) Why there are two cyclooxygenase isozymes. J Clin Investig 107:1491-1495.
27. Sorbera LA, Castaner J, Bayes M, and Silvestre JS (2002) Lumiracoxib. Drugs Future 27:740-747.
28. Thummel KE and Wilkinson GR (1998) In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol 38:389-430.
29. Vane JR (2000) The fight against rheumatism: from willow bark to COX-1 sparing drugs. J Physiol Pharmacol 51:573-586.
30. Weaver AL (2001) Rofecoxib: clinical pharmacology and clinical experience. Clin Ther 23:1323-1338.