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

• Published in: Biopharmaceutics & drug disposition Vol. 22; no. 6; pp. 231 - 242
• Main Authors: Reinoso, Raquel F., Farrán, Ramón, Moragón, Trinidad, García-Soret, Antonio, Martínez, Lluis
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.09.2001; Wiley
• Subjects: Administration, Oral; Animals; anti-inflammatory agents; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Area Under Curve; Biological and medical sciences; Biotransformation; Bones, joints and connective tissue. Antiinflammatory agents; cyclooxygenase-2; dog; Dogs; Female; Half-Life; Injections, Intravenous; Male; Medical sciences; Particle Size; pharmacokinetics; Pharmacology. Drug treatments; Pyrazoles - administration & dosage; Pyrazoles - pharmacokinetics; Pyrazoles - pharmacology; rat; Rats; Rats, Wistar; Species Specificity; Sulfonamides - administration & dosage; Sulfonamides - pharmacokinetics; Sulfonamides - pharmacology; Fissipedia; Prostaglandin-endoperoxide synthase; Carnivora; Intravenous administration; Rat; Enzyme; Rodentia; Single dose; Oral administration; Enzyme inhibitor; Non steroidal antiinflammatory agent; Vertebrata; Mammalia; Animal; Oxidoreductases; Pharmacokinetics; Dog
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.258

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.