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

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 (approximately 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.