Combination of bioactive phytochemical and synthetic anthelmintics: in vivo and in vitro assessment of the albendazole-thymol association

Abstract

The search of novel strategies is an urgent need considering the widespread increasing of anthelmintic resistance in livestock. Bioactive phytochemicals may contribute to improve parasite control by enhancing the effect of existing anthelmintic drugs. This work evaluated the in-vivo and in-vitro pharmaco-chemical interaction and the in-vivo efficacy of the combination of albendazole (ABZ) with a phenolic natural monoterpene, thymol (TML), in lambs naturally infected with resistant gastrointestinal nematodes. Thirty (30) lambs were allocated into three (3) experimental groups. Each group was treated orally with either ABZ (5 mg/kg), Thymol (150 mg/kg, twice every 24 h) or the co-administration of both compounds. Blood samples were collected between 0 and 51 h post-treatment and TML, ABZ and its metabolites were determined by HPLC. Individual faecal samples were collected at days -1 and 14 post-treatment to perform the faecal eggs count reduction test. Additionally, the effect of TML on the metabolic sulphoreduction and the sulphonation of ABZ sulphoxide was in-vitro assessed using ruminal content and liver microsomes, respectively. No changes on the pharmacokinetic behavior of ABZ sulphoxide were observed in the presence of the natural product (TML). In contrast, the ABZ sulphone Cmax and AUC were lower (p<0.05) in the co-administered animals (0.16±0.07 µg/mL y 3.63±1.21 µg.h/mL) compared with those that received ABZ alone (0.45±0.15 µg/mL and 9.50±2.84 µg.h/mL). TML was detected in the bloodstream between 1 and 51 h post-treatment, which indicates the time of target nematodes exposure to the bioactive monoterpene. However, the in-vivo efficacy of TML was 0% and the presence of TML did not increase the efficacy of ABZ. The presence of TML inhibited significantly (P< 0.05) the ruminal sulphoreduction and the hepatic sulphonation of ABZ sulphoxide. In-vivo pharmaco-parasitological studies are relevant to corroborate the adverse kinetic/metabolic interactions and the efficacy of bioactive natural products combined with synthetic anthelmintics.