Influence of P-glycoprotein inhibition on secretion of ivermectin and doramectin by milk in lactating sheep

The aim of to the present study was to evaluate the effects of verapamil (VER) on plasma pharmacokinetics of ivermectin (IVM) and doramectin (DOR) in lactating Istrian Pramenka dairy sheep and to investigate the role of P-glycoprotein (P-gp) in transport of avermectins into milk. Pharmacokinetics of IVM and DOR following subcutaneous administration of 0.2mg/kg b.w. was evaluated in four groups of sheep. They were administered either IVM or DOR alone or in combination with verapamil (VER) at a dose of 3.0mg/kg b.w., 3 times at 12h intervals. Blood plasma and milk samples were collected at defined time intervals over 30 days post-treatment to determine IVM and DOR concentration levels. Pharmacokinetic parameters in sheep injected with IVM or DOR alone corresponded to previously published values. Comparison between sheep injected with IVM only, and sheep injected with IVM in combination with VER (IVM+VER) showed significant difference in pharmacokinetic parameters in blood plasma. Area under the concentration-time curve (AUC) truncated at 2 days (AUC(2)) was 15 and 28 μg day/L for group IVM and IVM+VER, respectively. With co-administration of VER, apparent plasma clearance (Cl/F) and mean residence time (MRT) of IVM decreased from 135 to 116 L/day and from 5.8 to 3.8 days, respectively. Similar trends were observed for DOR (AUC(2) 48 vs. 68 μg day/L, Cl/F 61 vs. 46 L/day, and MRT 5.6 vs. 4.4 days for groups DOR and DOR+VER, respectively). This study confirms that co-administration of VER has a significant effect on pharmacokinetic parameters of subcutaneously administered IVM in blood plasma. The influence on DOR pharmacokinetics is much weaker. This could be either due to the difference in lipophilicity or the difference in affinity towards P-gp as a result of structural differences. No significant influence of VER on AUC ratio of IVM and DOR between milk and plasma was observed suggesting that P-gp does not govern transport of avermectins into milk.