Metabolism and pharmacokinetics of dothiepin.

1 Seven healthy volunteers received a single oral dose of 75 mg dothiepin. Plasma concentrations of dothiepin were measured by gas chromatography-mass fragmentography. 2 The plasma concentrations obtained were fitted to the equation Ct = Ae-a(t-tau) + Be-beta(t-tau) - Ce-ka(t-tau). The mean peak concentration was 47(33-71) microgram/l at 3(2-5) h. Mean estimates were as follows: absorption half life 1.2(0.07-3.0) h, distribution half-life 2.6(1.1-3.8) h, elimination half-life 22(14-40) h, apparent volume of distribution 45(20-92) l/kg, and oral clearance 1.36(0.88-1.8) l kg-1 h-1. 3 Blood concentrations of dothiepin were measured in comparison in five of the volunteers. The mean blood/plasma ratio was 0.7(0.6-0.8). 4 Plasma and blood concentrations of northiaden and blood concentrations of dothiepin S-oxide, two metabolites of dothiepin, were also measured. Dothiepin S-oxide was the major metabolic reaching a peak level of 81(34-150) microgram/l at 5(4-6) h. In comparison, northiaden reached a peak concentration of only 10 (3-21) microgram/l at 5 (4-9) h. The mean half-life of elimination of dothiepin S-oxide was 19 (13-35) h while that for northiaden was 33 (22-60) h.