Influence of dyslipidemia on moxidectin distribution in plasma lipoproteins and on its pharmacokinetics

Purpose: We studied the influence of dyslipemia on the distribution of moxidectin, a potent antiparasitic drug of the macrocyclic lactone (ML) family, in plasma lipoproteins and on its pharmacokinetic behaviour. Materials and Methods: Plasma samples from normolipidemic or dyslipidemic subjects were spiked with moxidectin (20 ng/ml). Rabbits fed with standard (n = 5) or cholesterol-enriched diet (n = 5) were injected subcutaneously with moxidectin (300 mu g/kg) and blood samples were collected over 32 days. Lipoproteins were separated from plasma samples by ultracentrifugation on density gradients. Moxidectin and lipids were measured in plasma and in lipoproteins and the pharmacokinetic parameters calculated. Results: In normolipidemic subjects or rabbits, the drug bound preferentially to HDL. In hyperlipidemic samples, moxidectin shifted to the VLDL-LDL fraction. In addition, hyperlipidemic rabbits had a 2.8-fold higher area under the plasma concentration versus time curve (AUC) and a lower clearance and volume of distribution when compared with controls. Conclusions: Dyslipidemia led to major changes in moxidectin plasma distribution and in drug disposition. Therefore, a high variability in moxidectin disposition might be expected in humans or animals liable to develop dyslipidemia, with a possible impact on the efficacy and safety of this class of drugs.