Effects of physiological covariables on pharmacokinetic parameters of clomipramine in a large population of cats after a single oral administration C. LAINESSE* D. FRANK   F. BEAUDRY* & M. DOUCET* *De ´partement de Biome ´decine Ve ´te ´rinaire, Faculte ´ de Me ´decine Ve ´te ´rinaire, Universite ´ de Montre ´al, St-Hyacinthe, QC, Canada;   De ´partement de Sciences Cliniques, Faculte ´ de Me ´decine Ve ´te ´rinaire, Universite ´ de Montre ´al, St-Hyacinthe, QC, Canada Lainesse, C., Frank, D., Beaudry, F., Doucet, M. Effects of physiological covari- ables on pharmacokinetic parameters of clomipramine in a large population of cats after a single oral administration. J. vet. Pharmacol. Therap. 30, 116–126. This study was conducted to confirm an interindividual variability in pharmacokinetic parameters of clomipramine in a large population of cats and to identify potential covariables that would explain the presence of such pharmacokinetic variability after a single dose of Clomicalm Ò . Clomipramine hydrochloride was administered orally according to a weight-dose chart from 0.32 to 0.61 mg/kg, to 76 cats and five blood samples were then taken by direct venipuncture at 1, 3, 6, 12, and 24 h. Plasma concentrations of clomipramine and desmethylclomipramine (DCMP) were measured by LC-MS/ MS. The Standard Two-Stage technique was used to assess differences and detect correlations between pharmacokinetic parameter estimates and individ- ual covariables. A large interindividual variability in all pharmacokinetic parameters (CV% 64–124) was detected. Statistically significant gender-related differences were detected in MR and Cl/F, where female cats had a higher mean MR (0.53) and faster Cl/F (0.36 L/hÆkg) than males (0.36 and 0.21 L/hÆkg, respectively). No correlation could be found between clomipramine AUC 0-24h or DCMP AUC 0-24h and sedation scores. Further feline studies are required to assess these findings after multiple dosing of clomipramine and DCMP to allow clinical extrapolation. (Paper received 6 July 2006; accepted for publication 10 November 2006) Miche `le Doucet, De ´partement de biome ´decine ve ´te ´rinaire, Faculte ´ de Me ´decine Ve ´te ´rinaire, Universite ´ de Montre ´al, St-Hyacinthe, QC J2S 7C6, Canada. E-mail: michele.doucet@umontreal.ca INTRODUCTION Clomipramine hydrochloride, a tricyclic antidepressant, is a selective serotonin (5-HT) re-uptake inhibitor while its active metabolite, desmethylclomipramine (DCMP), has shown to preferentially inhibit norepinephrine reuptake from the presy- naptic neuron in an in vitro rat cerebral cortex synaptosome model (Benfield et al., 1980). Over the years and through animal models and human clinical trials, several other receptors have shown to be involved in the delayed mode of action of this class of antidepressant such that the mixed monoaminergic effect that maintains functional homeostasis also includes desensitization of presynaptic 5-HT autoregulators and heteroreceptors, downreg- ulation of postsynaptic b-adrenoceptors and increased sensitivity of several postsynaptic 5-HT subtypes (Potter, 1996). Clomipramine has been used for the treatment of anxiety, fear, phobias, severe depression, and obsessive–compulsive behaviors in human patients (McTavish & Benfield, 1990, Gex-Fabry et al., 2000) and is recommended as an adjunct treatment for several behavioral problems, such as urine marking, aggression, excessive vocalization and compulsive behaviors in cats (Seksel & Lindeman, 1998; Litster, 2000; Pryor et al., 2001; King et al., 2004; Landsberg & Wilson, 2005), separation anxiety, storm phobia and compulsive behaviors in dogs (Podberscek et al., 1999; Seksel & Lindeman, 2001; Overall & Dunham, 2002; Crowell-Davis et al., 2003; Luescher, 2003; Gaulthier et al., 2005), and compulsive feather picking in birds (Grindlinger & Ramsay, 1991; Juabe-Diaz, 2000). In human patients, DCMP plasma concentrations are used to monitor and adjust therapy as a low ratio of DCMP C p /CMP C p correlates with successful clinical outcome and lower incidence of side effects (Gex-Fabry et al., 1990; Nielsen et al., 1996; Oesterheld & Kallepalli, 1997). A study in humans demonstrated metabolic differences between sexes and ages reflecting a decreased hydroxylation and glucuronidation clearances in female patients and in older patients (Gex-Fabry et al., 1990). Throughout the years, genetic metabolic polymorphism, physio- logical (age and gender), and environmental (smoking, alcohol consumption and comedication) factors as well as patient compliance have been identified as potential covariables to J. vet. Pharmacol. Therap. 30, 116–126, 2007. 116 Ó 2007 The Authors. Journal compilation Ó 2007 Blackwell Publishing Ltd