Ex vivo and in vivo pharmacological inte- raction between antiparasitic drugs and the phytochemical monoterpenes thymol and cinnamaldehyde

Abstract

Considering the increase of nematode resis-tance to the synthetic anthelmintic drugs, newcontrol strategies are urgently needed. While many phytochemical compounds show in vitroantiparasitic activity, their in vivo therapeutic potential remains underexplored. Both theex vivo and in vivo effects of cinnamaldehyde (CNM) and thymol (TML) on the doramectin(DRM) and levamisole (LVM) nematodicidal response were assessed in naturally infected lambs. The interaction on intestinal absorption/secretion by CNM, TML (1.5 mM) DRM and LVM(5 μM) was assessed using a diffusion chamber model with Rho123 (0.5 μM) as a substrate across lamb ileum tissue. Two in vivo trials(T1 and T2) examined the interactions between monoterpenes and the synthetic anthelmintics. In T1, CNM (100 mg/kg, orally at 0 and 24h) was combined with DRM (0.2 mg/kg, SC),with outcomes evaluated over two years. In T2,lambs received LVM (3.75 mg/kg, SC) alone orcombined with CNM or TML (80 mg/kg, SC at0 and 3 h). Drug plasma levels were measuredby HPLC and fecal egg count reduction (FECR) were used to assess efficacy. CNM and LVM decreased Rho123 efflux across lamb intestine,suggesting a drug transport-related interaction.In T1, co-administration with CNM increased DRM efficacy from 66.3% to 78.0% (first treat-ment year); however, no significant differences in efficacy or pharmacokinetic (PK) parameters were observed in the second year between the DRM and DRM+CNM groups. In T2, both CNMand TML enhanced LVM systemic exposure,increasing the area under the curve (AUC) by20–50%. Despite this PK interaction, treatment efficacy remained comparable for LVM+C-NM (55.5%), LVM+TML (57.8%) and LVM alone(51.4%). These results suggest that the phytochemicals CNM and TML may induce drug PK and/or pharmacodynamics interactions both ex-vivo and in-vivo. Overall, the findings offervaluable insights into the potential of phytochemicals as antiparasitic agents and on their interactions with conventional anthelmintics.