Pharmacokinetics of Dothiepin in Humans: A Single Dose Dose–Proportionality Study

Abstract

Dothiepin hydrochloride (N,N-dimethyldibenzo[b,e]thiepin-Δ11(6 H),γ-propylamine hydrochloride) is a tricyclic antidepressant which is structurally similar to amitriptyline. Twenty-seven healthy men received three single oral doses of 50-, 100-, and 150-mg dothiepin hydrochloride capsules in a three-way randomized, crossover dose–proportionality study. Plasma concentration-time profiles of dothiepin (1) were described by both one- and two-compartment models with first-order absorption. The total intrinsic clearance of dothiepin decreased from 165.5 to 121.1L/h as the dose was increased from 50 to 150mg, but there was no significant effect on the terminal half-life (∼20 h). Plasma concentration-time profiles of the three major metabolites of dothiepin, the S-oxide derivative of dothiepin, N,N-dimethyl[b,e]thiepin-Δ11(6 H),γ-propylamine 5-oxide (2), the demethyl derivative, N-methyldi-benzo[b,e]thiepin-Δ11(6 H),γ-propylamine (3) and the demethyl S-oxide derivative N-methyldibenzo[b,e]thiepin-Δ11(6 H),γ-propylamine 5-oxide (4), were described by a one-compartment model with apparent first-order formation. The AUC∞ values of the S-oxide 2 and the demethyl S-oxide 4 increased proportionally with dose. The dose proportionality of the demethyl metabolite 3 may not be ascertained from the data in this study. The corresponding half-lives of the three metabolites, which are dose independent, were approximately 24, 28, and 40 h, respectively.