PHARMACOKINETICS OF DERAMCICLANE IN DOGS AFTER SINGLE ORAL AND INTRAVENOUS DOSING AND MULTIPLE ORAL DOSING

The pharmacokinetics of a new serotonin 5-HT2 antagonist, deramciclane , was studied. Single oral doses of 1, 3, 6 and 10 mg kg(-1) and intra venous doses of 1, 3 and 6 mg kg(-1) were administered in beagle dogs. Moreover, the steady state pharmacokinetics of 1, 3 and 6 mg kg(-1) d oses were studied. Deramciclane was rapidly and completely absorbed fr om the gastrointestinal tract. Due to a moderate first-pass metabolism the absolute bioavailability was only 45-61%. Deramciclane had a larg e volume of distribution (32-37 L kg(-1)) because of its lipophilic na ture. Deramciclane was extensively metabolized after intravenous injec tion and only trace amounts of intact drug is excreted in the urine. T he total body clearance decreased (from 32 to 17 L h(-1)) as the dose increased. It is suggested that the metabolic capacity was not suffici ent to eliminate deramciclane in a linear manner with increasing dose. Therefore, deramciclane exhibited nonlinear pharmacokinetics as the A UC(0-infinity) increased disproportionally to the dose after both intr avenous and oral dosing. Formation of the active metabolite, N-desmeth yl deramciclane, was also nonlinear (p = 0.0002). At steady state dera mciclane accumulated less than 2-fold during repeated administration. (C) 1998 John Wiley & Sons, Ltd.