Pharmacokinetics of clomipramine, an antidepressant, in poloxamer 407-induced hyperlipidaemic model rats

Objective This study was undertaken to investigate the effects of hyperlipidaemia on the pharmacokinetics of clomipramine, an antidepressant, particularly addressing the change of clomipramine distribution to plasma components in poloxamer 407‐induced hyperlipidaemia model rats. Methods Clomipramine pharmacokinetic studies in hyperlipidaemic rats were performed with clomipramine continuous infusion. Furthermore, clomipramine protein binding and distribution to the brain and plasma components such as lipoproteins were investigated. Key findings Mean plasma concentration of clomipramine at steady state during continuous infusion (17.5 µg/min/kg) in hyperlipidaemic rats (0.45 ± 0.01 µg/ml) was significantly higher than that in the control rats (0.30 ± 0.02 µg/ml). However, the amount of clomipramine in the brain in hyperlipidaemic rats (0.31 ± 0.06 µg/g) was dramatically lower than in the control rats (1.89 ± 0.13 µg/g). However, the plasma unbound fraction in hyperlipidaemic rats (0.98 ± 0.05%) was significantly lower than that of the control rats (6.51 ± 0.62%). Conclusions Lower distribution to the brain and lower plasma clearance of clomipramine in hyperlipidaemic rats resulted from lower plasma unbound fraction because of higher lipid‐rich protein contents in blood. Results of this study provide useful information for dosage adjustment of clomipramine in hyperlipidaemia.