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.

Phytotherapy represents a promising field for developing new therapeutic strategies, either by acting as antiparasitic agents themselves or by enhancing the efficacy of synthetic drugs. The present study evaluated the in vivo pharmacokinetic and pharmacodynamic interactions following the administration of doramectin, either alone or in combination with cinnamaldehyde and pink grapefruit essential oil (CNM–PGF). Additionally, ex vivo P-glycoprotein-mediated interactions were assessed at the intestinal level. Higher efficacy against Haemonchus contortus was observed with the combined treatment of doramectin plus phytochemicals or loperamide. Although phytochemicals and loperamide reduced the ex vivo efflux of rhodamine 123, no pharmacokinetic interactions were detected in vivo. The enhanced efficacy is most likely attributable to localized drug–drug interactions and increased drug availability at the parasite interface. Based on the results obtained, the best treatment would be the combination of DRM with phytochemicals such as CNM–PGF and loperamide. However, a pharmaceutical formulation that allows sustained in vivo interaction between these compounds is needed.