Metabolic pathways of anthelmintic drug monepantel in sheep and in its parasite (Haemonchus contortus)

Abstract

Monepantel (MOP) is a new anthelmintic drug intended for the treatment and control of gastrointestinal roundworms (nematodes) infection and associated disease in sheep. The aim of our study was to find out metabolic pathways of MOP in sheep in vivo and in its parasite Haemonchus contortus ex vivo. MOP biotransformation in two H. contortus strains with different sensitivity to anthelmintics was also compared. Ultra high-performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) technique is used for the identification of MOP metabolites in ovine urine, faeces, and nematodes. MOP biotransformation study in sheep in vivo led to the identification of 13 MOP metabolites; 7 of them have not been described previously in in vitro study. The study of MOP biotransformation in H. contorus ex vivo reveals four MOP metabolites. The nitrile hydrolysis as a new biotransformation pathway in helminths ex vivo is reported here for the first time. Unlike sheep, H. contorus nematodes are not able to metabolize MOP via phase II biotransformation. Nematodes of resistant White river (WR) strain form more types of MOP metabolites than nematodes of sensitive inbred susceptible Edinburgh (ISE) strain. Based on obtained results, schemes of metabolic pathways of MOP in sheep and nematodes are proposed.

A perspective on genomic-guided anthelmintic discovery and repurposing using Haemonchus contortus

“…Then, metabolic effectors could be studied in vitro using microsomes (phase I drug metabolism reactions) and hepatocytes (both phase I and II drug metabolism reactions) (e.g. Jia and Liu 2007;Vokral et al, 2013;Stuchlikova et al, 2014).…”

Reliable reference gene selection for quantitative real time PCR in Haemonchus contortus

“…The maintenance of H. contortus ISE and WR isolates were as described in our previous reports [15][16][17].…”

The role of drug efflux systems in anthelmintic resistance in parasitic nematodes

“…In the presence of forskolin, the detoxification of BFA by conjugation with cysteine was increased. Stuchlíková et al (2014) found that a resistant strain of H. contortus produced more MPL metabolites than worms of sensitive strain which suggests that resistant worms may have more active biotransformation enzymes. The results of section 2.1 showed that the effects of MDRIs in increasing the efficacy of anthelmintics were much greater in WAL larvae as compared to Kirby.…”

“…contortus worms are able to metabolise monepantel via S-oxidation and hydrolytic pathways (Stuchlíková et al, 2014), however, there is no evidence that these pathways are increased in resistant worms. The interaction of monepantel with drug efflux pathways (e.g.…”

“…Stuchlíková et al (2014) reported on the metabolic pathways of MPL in H. contortus, as measured ex vivo (Fig. 2.6).…”