Pharmacokinetics of clomipramine in dogs following single-dose and repeated-dose oral administration

Abstract

Objective - To determine pharmacokinetics of clomipramine and its principle metabolite (desmethyl-clomipramine) in the plasma of dogs following single-dose and repeated-dose oral administration at various dosages. Animals - 9 male and 9 female Beagles. Procedures - Clomipramine was administered orally at a dose of 1, 2, or 4 mg/kg to 3 male and 3 female dogs, first as a single dose and then, after an interval of 14 days, twice daily for 10 days. Plasma clomipramide and desmethylclomipramide concentrations were measured by use of a gas chromatography with mass-selection method. Results - Dose- related accumulation was detected following repeated-dose administration. Accumulation ratios after administration of clomipramine at dosages of 1, 2, and 4 mg/kg twice daily were 1.4, 1.6, and 3.8, respectively, for clomipramine and 2.1, 3.7, and 7.6, respectively, for desmethylclomipramine. Terminal half-life increased slightly (1.6-fold for clomipramine and 1.2-fold for desmethylclomipramine) with repeated-dose administration but remained short in all groups (≤ 4 hours). Steady state was reached within 4 days in all animals. Ratios of the areas under the concentration versus time curves from time 0 to 12 hours for clomipramine and desmethylclomipramine were 3.9, 3.1, and 1.5 after repeated administration at dosages of 1, 2, and 4 mg/kg every 12 hours, respectively. Areas under the concentration versus time curve, mean residence times, and terminal half-lives were not significantly different between male and female dogs. Conclusions and Clinical Relevance - Repeated administration of clomipramine results in higher concentrations of clomipramine than desmethyl-clomipramine in dogs.