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

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  • 1 Novartis Animal Health, Werk Rosenthal, Basel, CH-4002, Switzerland.
  • | 2 Novartis Animal Health, Centre de Recherche Santé Animale, St Aubin, CH-1566, Switzerland.
  • | 3 Novartis Crop Protection, Stein, CH-4432, Switzerland.
  • | 4 Novartis Animal Health, Werk Rosenthal, Basel, CH-4002, Switzerland.

Abstract

Objective—To determine pharmacokinetics of clomipramine and its principle metabolite (desmethylclomipramine) in the plasma of dogs following singledose 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 clomipramine and desmethylclomipramine 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 desmethylclomipramine in dogs. (Am J Vet Res 2000;61:80–85)

Abstract

Objective—To determine pharmacokinetics of clomipramine and its principle metabolite (desmethylclomipramine) in the plasma of dogs following singledose 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 clomipramine and desmethylclomipramine 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 desmethylclomipramine in dogs. (Am J Vet Res 2000;61:80–85)