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Research ArticleArticle

Role of Human Liver Cytochrome P4503A in the Metabolism of Etoricoxib, a Novel Cyclooxygenase-2 Selective Inhibitor

Kelem Kassahun, Ian S. McIntosh, Magang Shou, Deborah J. Walsh, Carey Rodeheffer, Donald E. Slaughter, Leslie A. Geer, Rita A. Halpin, Nancy Agrawal and A. David Rodrigues
Drug Metabolism and Disposition June 2001, 29 (6) 813-820;
Kelem Kassahun
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Ian S. McIntosh
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Magang Shou
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Deborah J. Walsh
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Carey Rodeheffer
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Donald E. Slaughter
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Leslie A. Geer
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Rita A. Halpin
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Nancy Agrawal
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A. David Rodrigues
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Abstract

Etoricoxib, a potent and selective cyclooxygenase-2 inhibitor, was shown to be metabolized via 6′-methylhydroxylation (M2 formation) when incubated with NADPH-fortified human liver microsomes. In agreement with in vivo data, 1′-N′-oxidation was a relatively minor pathway. Over the etoricoxib concentration range studied (1–1300 μM), the rate of hydroxylation conformed to saturable Michaelis-Menten kinetics (apparent K m = 186 ± 84.3 μM; V max = 0.76 ± 0.45 nmol/min/mg of protein; mean ± S.D., n = 3 livers) and yielded a V max/Km ratio of 2.4 to 7.3 μl/min/mg. This in vitroV max/K m ratio was scaled, with respect to yield of liver microsomal protein and liver weight, to obtain estimates of M2 formation clearance (3.1–9.7 ml/min/kg of b.wt.) that agreed favorably with in vivo results (8.3 ml/min/kg of b.wt.) following i.v. administration of [14C]etoricoxib to healthy male subjects. Cytochrome P450 (P450) reaction phenotyping studies—using P450 form selective chemical inhibitors, immunoinhibitory antibodies, recombinant P450s, and correlation analysis with microsomes prepared from a bank of human livers—revealed that the 6′-methyl hydroxylation of etoricoxib was catalyzed largely (∼60%) by member(s) of the CYP3A subfamily. By comparison, CYP2C9 (∼10%), CYP2D6 (∼10%), CYP1A2 (∼10%), and possibly CYP2C19 played an ancillary role. Moreover, etoricoxib (0.1–100 μM) was found to be a relatively weak inhibitor (IC50 > 100 μM) of multiple P450s (CYP1A2, CYP2D6, CYP3A, CYP2E1, CYP2C9, and CYP2C19) in human liver microsomes.

Footnotes

  • Send reprint requests to: Dr. Kelem Kassahun, Department of Drug Metabolism, Merck Research Laboratories, Sumneytown Pike, P.O. Box 4, WP75A-203, West Point, PA 19486-0004. E-mail:kelem_kassahun{at}merck.com

  • 1 Abbreviations used are: NSAID, nonsteroidal anti-inflammatory drug; COX, cyclooxygenase; P450, cytochrome P450; HPLC, high-performance liquid chromatography;K m, apparent Michaelis constant,V max, maximal initial reaction velocity; CLint, intrinsic clearance (V max/K m) in vitro (CLint, in vitro) or in vivo (CLint, in vivo); f u, p, fraction of drug unbound in plasma; f u, inc, fraction of drug unbound in the in vitro incubation (e.g., microsomes); CLp, plasma clearance after i.v. dosing; CLr, renal clearance;Q h, b, hepatic blood flow; B/P, blood-to-plasma ratio; f m, fraction of etoricoxib dose excreted in urine and feces as M2 and M3;f m,CYP, fraction of metabolism catalyzed by P450; LC/MS, liquid chromatography/mass spectrometry; MS, mass spectrometry.

    • Received October 19, 2000.
    • Accepted February 9, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (6)
Drug Metabolism and Disposition
Vol. 29, Issue 6
1 Jun 2001
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Research ArticleArticle

Role of Human Liver Cytochrome P4503A in the Metabolism of Etoricoxib, a Novel Cyclooxygenase-2 Selective Inhibitor

Kelem Kassahun, Ian S. McIntosh, Magang Shou, Deborah J. Walsh, Carey Rodeheffer, Donald E. Slaughter, Leslie A. Geer, Rita A. Halpin, Nancy Agrawal and A. David Rodrigues
Drug Metabolism and Disposition June 1, 2001, 29 (6) 813-820;

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Research ArticleArticle

Role of Human Liver Cytochrome P4503A in the Metabolism of Etoricoxib, a Novel Cyclooxygenase-2 Selective Inhibitor

Kelem Kassahun, Ian S. McIntosh, Magang Shou, Deborah J. Walsh, Carey Rodeheffer, Donald E. Slaughter, Leslie A. Geer, Rita A. Halpin, Nancy Agrawal and A. David Rodrigues
Drug Metabolism and Disposition June 1, 2001, 29 (6) 813-820;
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