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
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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
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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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