Integrated pharmacological evaluation of the combination of synthetic anthelmitics and bioactive phytochemicals: In-vitro and in vivo studies

Abstract

In a context of increasing anthelmintic resistance, combination of synthetic anthelmintics with bioactive phytochemicals may be a pharmacological tool for improving the nematode control in livestock. The coadministration of natural compounds and anthelmintics may lead to kinetic/dynamic interactions. This work evaluated the drug-drug interactions between synthetic anthelmintics and bioactive phytochemicals at the metabolism and drug transport level. The impact of these interactions on drug efficacy was also studied. Trial 1 include in vitro and in vivo the combination of thymol (TML) and albendazole (ABZ). The stability of TML (800 µg/ml) in sheep ruminal content and its effects (5 mM) on the metabolism of ABZ in sheep liver microsomes were evaluated. The in vivo plasma concentrations and efficacy of the combination were studied in lambs naturally infected with resistant nematodes. TML was stable in sheep ruminal content and inhibited (P<0.05) the ruminal sulphoreduction of ABZ sulphoxide. Besides, TML markedly inhibited the hepatic FMO-dependent S-oxygenation of ABZ (54.1±11.6%, P<0.05) and the sulphonation of ABZ sulphoxide (P<0.05). However, the in vivo pharmacokinetic changes did not improve the efficacy of ABZ after the combined treatment with TML. In trial 2 the combination of carvone (CVN) and abamectin (ABM) was studied. The modulation of CVN on the P-glycoprotein-mediated transport of Rhodamine 123 (Rho-123) was assessed using the intestinal explants model. The in vivo effect of CVN on ABM kinetics disposition and efficacy was evaluated in lambs infected with resistant nematodes. The presence of CVN increased the Rho123 accumulation in intestinal explants (60% P<0.05). In vivo, the coadministration of CVN prolong the absorption half-life of ABM (57 % P<0.05) and increased the efficacy from 94,9% to 99,8%. In-vitro-in vivo trials are necessary to corroborate the clinical relevance of the combinations of bioactive phytochemicals and anthelmintics.