Pharmacokinetics of Tropatepine in Healthy Volunteers

Abstract

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 (20mg/day) in 2 healthy volunteers. Pharmacokinetic parameters of tropatepine and the desmethylated active metabolite nortropatepine were estimated. Clearance following intravenous administration (19 \+- 4 L/h) and after multiple-dose oral administration (27 to 28 L/h) were stable given a bioavailability of 76.1 \+- 24%. A good correlation was found between dose (10, 15 and 20mg) and maximum plasma concentration (Cmax) [6.5 \+-4.5 \gmg/L, 8.5 \+- 6.2 \gmg/Land 18.2 \+- 8.2 \gmg/L, respectively] and total quantity of tropatepine excreted in urine over a period of 120 hours (200 \+- 67\gmg, 254 \+- 93\gmg and 351 \+- 139\gmg, 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 Cmax of 29 \+- 1.4 \gmg/L to a Cmin of 13.8 \+- 1.1 \gmg/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 \+- 7.95 hours), the range of variations in plasma concentration was smaller than that of tropatepine, i.e. between a Cinmin of 6.5 \+-1.5 |J.g/L and a Cinmax of 9.5 \+- 3.2 \gmg/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 (152%) than that after single-dose administration (62%).