Absorption, Metabolism, and Excretion of Etoricoxib, a Potent and Selective Cyclooxygenase-2 Inhibitor, in Healthy Male Volunteers

Abstract

ABSTRACT:[ 14 C]Etoricoxib (100 Ci/dose) was administered to six healthy male subjects (i.v., 25 mg; p.o., 100 mg). Following the i.v. dose, the plasma clearance was 57 ml/min, and the harmonic mean half-life was 24.8 h. Etoricoxib accounted for the majority of the radioactivity (ϳ75%) present in plasma following both i.v. and p.o. doses. The oral dose, administered as a solution in polyethylene glycol-400, was well absorbed (absolute bioavailability of ϳ83%). Total recovery of radioactivity in the excreta was 90% (i.v.) and 80% (p.o.), with 70% (i.v.) and 60% (p.o.) excreted in urine and 20% in feces after either route of administration. Radiochromatographic analysis of the excreta revealed that etoricoxib was metabolized extensively, and only a minor fraction of the dose (<1%) was excreted unchanged. Radiochromatograms of urine and feces showed that the 6-carboxylic acid derivative of etoricoxib was the major metabolite observed (>65% of the total radioactivity). 6-Hydroxymethyl-etoricoxib and etoricoxib-1-N-oxide, as well as the O-␤-D-glucuronide conjugate and the 1-N-oxide derivative of 6-hydroxymethyl-etoricoxib, were present in the excreta also (individually, <10% of the total radioactivity). In healthy male subjects, therefore, etoricoxib is well absorbed, is metabolized extensively via oxidation (6-methyl oxidation >1-N-oxidation), and the metabolites are excreted largely in the urine.

Oral voriconazole and miconazole oral gel produce comparable effects on the pharmacokinetics and pharmacodynamics of etoricoxib

“…This reaction is mainly catalyzed by CYP3A (60%), but the rest is catalyzed equally between CYP2C9, CYP2C19, CYP2D6, and CYP1A2 [2,3]. Correspondingly, previous in vitro studies have indicated that miconazole is a nonselective inhibitor of several CYPs, namely CYP3A, 2C9, 2C19, 1A2, 2A6, and 2B6 [4][5][6].…”

“…Oral bioavailability of etoricoxib tablets is nearly 100% [1]. Despite its negligible first-pass metabolism, the elimination of etoricoxib is characterized by extensive metabolism, with less than 1% of an oral dose detected as unchanged drug in urine [2]. In vitro studies indicate that cytochrome P450 3A (CYP3A) is the most important enzyme catalyzing the primary metabolic pathway of etoricoxib (60%), with CYP2C9, CYP2D6, CYP1A2, and CYP2C19 each contributing about 10% [3].…”

Effects of rofecoxib on lipid oxidation in plasma and aortas of rats

“…For evaluation of pro-oxidant activity, the same treatment was performed in the presence of FeSO 4 (400 μM for plasma and 100 μM for aortic homogenate), to which (+)-ascorbic acid (10 mM for plasma and 500 μM for aortic homogenate) was added as a positive control for the Fenton reaction instead of the COX-2 inhibitors. Celecoxib (4 μM; Celecox® product information, Astellas Pharma Inc., Apr 2014), valdecoxib (1 μM: BEXTRA®, product information, Pfizer, July 2003) and etoricoxib (8 μM, Rodrigues et al, 2003) were also used for the experiments. The concentration of each COX-2 inhibitor was about the same as the maximum concentration when used clinically or in clinical trials, except for 200 μM rofecocxib.…”

IMPACT OFCYP2C9GENOTYPE ON PHARMACOKINETICS: ARE ALL CYCLOOXYGENASE INHIBITORS THE SAME?: TABLE 1

“…14 C]etoricoxib, and it can be estimated that about 75% of the dose (f m ϳ0.8) is cleared via P450-dependent 6Ј-methyl hydroxylation (Kassahun et al, 2001;Rodrigues et al, 2003). As in the case of rofecoxib, therefore, CYP2C9 plays a relatively minor role in the overall clearance of etoricoxib (f m ⅐ f m,CYP2C9(EM) Յ 0.2) ( Table 1).…”

“…In comparison to rofecoxib, the metabolic profile of etoricoxib is less complex and involves only P450-dependent 6Ј-methyl hydroxylation and 1Ј-N-oxidation as primary clearance pathways (Kassahun et al, 2001;Rodrigues et al, 2003). The 6Ј-methylhydroxy metabolite is major in human liver microsomes and is oxidized further to 6Ј-carboxy etoricoxib in the presence of cofactorfortified human liver cytosol.…”