Pharmacokinetics of E-6087, a new anti-inflammatory agent, in rats and dogs

Authors

  • Raquel F. Reinoso,

    1. Department of Pharmacokinetics and Drug Metabolism, Laboratorios Dr. Esteve S.A., Av. Mare de Déu de Montserrat 221, 08041 Barcelona, Spain
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  • Ramón Farrán,

    1. Department of Pharmacokinetics and Drug Metabolism, Laboratorios Dr. Esteve S.A., Av. Mare de Déu de Montserrat 221, 08041 Barcelona, Spain
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  • Trinidad Moragón,

    1. Department of Pharmacokinetics and Drug Metabolism, Laboratorios Dr. Esteve S.A., Av. Mare de Déu de Montserrat 221, 08041 Barcelona, Spain
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  • Antonio García-Soret,

    1. Department of Pharmacokinetics and Drug Metabolism, Laboratorios Dr. Esteve S.A., Av. Mare de Déu de Montserrat 221, 08041 Barcelona, Spain
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  • Lluis Martínez

    Corresponding author
    1. Department of Pharmacokinetics and Drug Metabolism, Laboratorios Dr. Esteve S.A., Av. Mare de Déu de Montserrat 221, 08041 Barcelona, Spain
    • Department of Pharmacokinetics and Drug Metabolism. Laboratorios Dr. Esteve S.A., Av. Mare de Déu de Montserrat 221, 08041 Barcelona, Spain
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Abstract

The pharmacokinetics of E-6087, a newly developed cyclooxygenase-2 inhibitor, was studied in rats and dogs after single oral and intravenous doses. In both animal species, E-6087 was characterized by a long elimination half-life (20–35 h), a low plasma clearance (0.10–0.22 l h−1 kg−1) and a relatively large volume of distribution (2–6 l kg−1). Oral bioavailability was lower in dogs than in rats whereas a faster elimination was found in rats. Multiple peaks were present regardless of administration route and animal species, suggesting the existence of enterohepatic circulation. Gender effect on the pharmacokinetics of E-6087 was only found in rats, with greater exposure and longer elimination in females than in males. Food intake reduced the bioavailability (∼22%) with no apparent changes in the absorption rate. After oral dosing of 1, 5 and 25 mg kg−1 to rats, linearity was lost at the highest dose due to the low aqueous solubility of E-6087. Drug absorption was improved by micronization. E-6087 and E-6132, (a pharmacologically active metabolite), showed different pharmacokinetics. The higher percentage of E-6087 at early times suggests that E-6087 is the main compound responsible for in vivo activity, although E-6132 would contribute to the activity at later times. Copyright © 2001 John Wiley & Sons, Ltd.

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