title: Pharmacokinetics of E-6087, a new anti-inflammatory agent, in rats and dogs.
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 (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.
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Laboratorios Dr. Esteve S.A., Av. Mare de Déu de Montserrat 221, 08041 Barcelona, Spain.
authors.forename: R F
authors.initials: RF
authors.lastname: Reinoso
authors.forename: R
authors.initials: R
authors.lastname: Farrán
authors.forename: T
authors.initials: T
authors.lastname: Moragón
authors.forename: A
authors.initials: A
authors.lastname: García-Soret
authors.forename: L
authors.initials: L
authors.lastname: Martínez
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001711:Biotransformation; D004285:Dogs; D005260:Female; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D010316:Particle Size; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011720:Pyrazoles; D013449:Sulfonamides; C427706:enflicoxib; D000096926:Benzenesulfonamides