Clinical Pharmacokinetics of Dothiepin

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Abstract
The pharmacokinetics of dothiepin were evaluated in 9 depressed patients following a single oral dose of 75mg. Blood and plasma concentrations of dothiepin and 2 major metabolites, northiaden and dothiepin S-oxide, were measured by gas chromatography/mass fragmentography. The mean (±SD) peak plasma concentrations of dothiepin were 49 ±27 μg/L at 3 ± l.2h. Mean (± SD) estimates of other parameters were as follows: absorption half-life 1.1 ± 1.1h; distribution half-life 2.2 ± 0.8h; elimination half-life 25 ± 7h; apparent volume of distribution 70 ± 62 L/kg; and oral clearance 2.1 ± 1.6 L/kg/h. The mean (±SD) peak plasma concentration of dothiepin S-oxide was 125 ± 43 μg/L at 3.5 ± 1.3h with an elimination half-life of 22 ± 12h. The mean peak plasma concentration of northiaden was 6 ± 3 μg/L at 4.5 ± 1.1h, with an elimination half-life of 31 ±12h. No significant differences were found in pharmacokinetic parameters compared with a previous study in 7 healthy volunteers. When data for the patients and healthy volunteers were combined (n = 16), pharmacokinetic parameters were not found to be affected by age. However, a significant difference was found between males and females for the elimination half-lives of dothiepin and northiaden, and for the apparent volume of distribution of dothiepin. The 24-hour blood/plasma concentrations of dothiepin and dothiepin S-oxide accurately predicted the steady-state concentrations obtained following 4 weeks’ treatment with dothiepin 150mg nocte.