Phytochemicals in Gastrointestinal Nematode Control: Pharmacokinetic–Pharmacodynamic Evaluation of the Ivermectin plus Carvone Combination

SIMPLE SUMMARY: In the last 50 years, limited modern drugs with new mechanisms of action have been incorporated; consequently, drug resistance has increased worldwide. Thus, the search for alternative pharmacological tools is a priority in ruminant production systems. Historically, natural products have played a relevant role in drug discovery. The anthelmintic activity of various phytochemicals has mainly been studied in vitro, whereas the in vivo characterization of their pharmacological properties is a challenge for upcoming years. The administration route and pharmaceutical formulation directly influence the drug concentration attained in the target parasites and, therefore, the resultant pharmacological effect. Here, we conducted an integrated pharmacological study to evaluate the combined administration of ivermectin and carvone to lambs infected with resistant nematodes. Although carvone showed a moderate in vivo anthelmintic effect and enhanced the ivermectin systemic availability after their coadministration in lambs, the concentrations attained in target tissues and in parasites were not sufficient for obtaining optimal efficacy. Innovative pharmaceutical formulations are necessary to establish phytochemicals as a useful pharmacological tool for controlling nematodes in ruminants. ABSTRACT: A wide variety of plant-derived phytochemicals with anthelmintic effects have been described. Most of them have shown activity against parasites in vitro but have not been extensively explored in vivo. The aim of the current work was to study the pharmacokinetic–pharmacodynamic relationship of the combined administration of carvone (R-CNE) and ivermectin (IVM) to lambs. Three trials were conducted to evaluate the pharmacological interaction between R-CNE and IVM in lambs infected with resistant nematodes. Drug concentrations were measured in plasma, target tissues, and H. contortus by HPLC with fluorescent (IVM) and ultraviolet (R-CNE) detection. The effect of both compounds on parasites was estimated by the fecal egg count reduction. Coadministration with R-CNE significantly increased the plasma bioavailability of IVM. R-CNE showed a moderate anthelmintic effect, which was greater on the susceptible isolate of H. contortus. After the combination of R-CNE and IVM as an oral emulsion, both compounds were quantified in H. contortus recovered from infected lambs. However, R-CNE concentrations were much lower than those reported to achieve anthelmintic effects in the in vitro assays. Optimization of the pharmaceutical formulation, dose rate, and administration schedule is needed to take advantage of the intrinsic anthelmintic activity of phytochemicals.