Comparative pharmacokinetics of deramciclane in rat, dog, rabbit and man after the administration of a single oral dose of 3 mg kg-1

Abstract

A comparative pharmacokinetic study of deramciclane fumarate (EGIS-3886), a new 5-HT2 antagonist with anxiolytic activity, was performed in rats, dogs, rabbits and healthy volunteers after the administration of a single oral dose of 3 mg kg−1. Considerable inter-species differences were revealed, particularly with respect to Cmax, AUC0-· and tβ1/2 values. Deramciclane showed rapid absorption in all cases (tmax: 0·3-2·6 h), whereas its elimination differed in different species (tβ1/2: 4·05–12·00 h in animals and 31·61 h in man). After the administration of a single 3 mg kg−1 oral dose of deramciclane, the AUC0-· value of the parent compound showed a significant species difference. The AUC0-· in rats, rabbits and dogs were 0·3, 13 and 21%, respectively, of that in man. The percentile ratio of unchanged deramciclane and total radioactivity (RDERAM) appeared to be extremely low and varied between 0·2 and 4·6%. The Vd kg−1 values suggested strong tissue binding in all the species studied. The plasma levels and pharmacokinetic parameters of N-desmethyl-deramciclane metabolite (EGIS-7056) were also studied and determined in the above species. The comparative pharmacokinetic study of deramciclane indicated an intensive biotransformation in all species although the rate of biotransformation appeared to be species-dependent.