Tropatepine is a compound with central anticholinergic properties that has been used in the treatment of neuroleptic-induced extrapyramidal syndrome. In this study, we report the plasma pharmacokinetics of tropatepine after intravenous and oral administration (20mg) in 8 healthy volunteers, after oral administration of different doses (10, 15 and 20mg) in 12 healthy volunteers, and following administration of multiple dosages of the drug (20 mgsol;day) in 2 healthy volunteers. Pharmacokinetic parameters of tropatepine and the desmethylated active metabolite nortropatepine were estimated. Clearance following intravenous administration (19 plusmn; 4 Lsol;h) and after multiple-dose oral administration (27 to 28 Lsol;h) were stable given a bioavailability of 76.1 plusmn; 24percnt;. A good correlation was found between dose (10, 15 and 20mg) and maximum plasma concentration (Cmax) lsqb;6.5 plusmn; 4.5 mgr;gsol;L, 8.5 plusmn; 6.2 mgr;gsol;L and 18.2 plusmn; 8.2 mgr;gsol;L, respectivelyrsqb; and total quantity of tropatepine excreted in urine over a period of 120 hours (200 plusmn; 67mgr;g, 254 plusmn; 93mgr;g and 351 plusmn; 139mgr;g, respectively). Such a correlation and the stable clearance confirmed a good linearity in plasma concentrations. Time to reach Cmax(tmax) was 6 to 7 hours for tropatepine and nortropatepine. This delay and the half-life of tropatepine (around 40 hours) were long enough to allow daily administration. However, plasma concentrations varied from a Cmaxof 29 plusmn; 1.4 mgr;gsol;L to a Cminof 13.8 plusmn; 1.1 mgr;gsol;L. This doubling in concentration led to the fractionation of the daily dose. Divisible tablets of 5mg have been prepared by Diamant Laboratories. Since the half-life of nortropatepine is long (65.5 plusmn; 7.95 hours), the range of variations in plasma concentration was smaller than that of tropatepine, i.e. between a Cminof 6.5 plusmn; 1.5 mgr;gsol;L and a Cmaxof 9.5 plusmn; 3.2 mgr;gsol;L. Tropatepine undergoes important metabolism, but nortropatepine is not the main metabolite. After multiple-dose administration, the ratio of urinary excretion of nortropatepine to tropatepine was higher (152percnt;) than that after single-dose administration (62percnt;).
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