Verapamil modifies maternal pharmacokinetics and increases the transplacental exchange of moxidectin in pregnant sheep

A study was performed in pregnant sheep at 120-128 d of gestational age, to evaluate the effect of the co-administration of moxidectin (MXD) and verapamil (Vpm) on maternal and foetal disposition kinetics after intravenous administration of MXD. Five pregnant Suffolk Down sheep of 60.8 ± 5.9 kg body weight (bw) were surgically prepared to insert polyvinyl catheters in the foetal femoral vein. The ewes were subcutaneously treated with Vpm (2.5 mg/kg × 3 doses at 12 h intervals) and 0.2 mg/kg MXD intravenously. Maternal and foetal blood samples were taken before and after MXD administration and during a 144 h post-treatment period. Samples were analysed by liquid chromatography (HPLC). A non-compartmental pharmacokinetic analysis was performed. Low levels of maternal MXD plasma concentrations and high volume of distribution and clearance values were found after co-administration of Vpm/MXD. The ratio between foetal and maternal total area under time-concentration curve (AUC) was 31.8 ± 13.7%, which is higher than that described for foetuses whose mothers were treated with MXD alone. The results of this study demonstrate that pharmacological blockage of P-glycoprotein with Vpm, increases both the maternal volume of distribution, as well as the transplacental transfer of MXD to the foetal circulation.