Influence of verapamil on pharmacokinetics and transplacental transfer of ivermectin in sheep

Abstract

In pregnant sheep at 120–128 days of gestational age, a study was done to evaluate the effect of the co-administration of verapamil (Vpm) and ivermectin (IVM) on the maternal and fetal disposition kinetics after intravenous administration of IVM. Ten pregnant Suffolk Down sheep of 63.5 ± 6.6 kg body weight (bw) were surgically prepared to insert polyvinyl catheters in the fetal femoral artery and vein and amniotic sac. The ewes were randomly assigned to two experimental groups. In Group 1 (control), 5 ewes were treated with an intravenous bolus of 0.2 mg IVM/kg bw. In Group 2 (Vpm-IVM), 5 ewes were subcutaneously treated with Vpm (2.5 mg/kg × 3 doses at 12 h intervals) and 0.2 mg/kg IVM by intravenous route. Maternal and fetal blood samples were taken before and after IVM administration during a 144 h post-treatment period. Samples were analyzed by liquid chromatography (HPLC). A non-compartmental pharmacokinetic analysis was performed and statistical differences were determined using the Mann–Whitney U-test. Significantly higher IVM levels in maternal plasma concentrations were determined after co-administration of Vpm/IVM compared with the group treated with IVM alone. Significant decreases in the volume of distribution and in the half-life of elimination ( t ½ β ) were observed in the Vpm/IVM treated group. A significantly faster ( T max) and higher ( C max) ( P < 0.05) increase in IVM fetal plasma concentrations were observed in the group of fetuses from pregnant ewes treated with Vpm/IVM. The results of our study support the hypothesis that pharmacological blockage of P-glycoprotein with Vpm can increase the transfer of IVM to fetal circulation.