Hepatic biotransformation pathways and ruminal metabolic stability of the novel anthelmintic monepantel in sheep and cattle

BALLENT M, ,; VIRKEL G,; MATÉ L; VIVIANI P,; BALLENT M, VIRKEL G, MATÉ L, VIVIANI P, LANUSSE C, LIFSCHITZ A.; LIFSCHITZ A.

JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2016 vol. 39 p. 488 - 496

0140-7783

Monepantel (MNP) is a new amino-acetonitrile derivative anthelmintic drugused for the treatment of gastrointestinal (GI) nematodes in sheep. The presentwork investigated the main enzymatic pathways involved in the hepaticbiotransformation of MNP in sheep and cattle. The metabolic stability inruminal fluid of both the parent drug and its main metabolite (monepantelsulphone, MNPSO2) was characterized as well. Additionally, the relative distribution of both anthelmintic molecules between the fluid and particulatephases of the ruminal content was studied. Liver microsomal fractions fromsix (6) rams and five (5) steers were incubated with a 40 lM of MNP. Heatpretreatment (50 °C for 2 min) of liver microsomes was performed for inactivation of the flavin-monooxygenase (FMO) system. Additionally, MNP wasincubated in the presence of 4, 40, and 80 lM of methimazole (MTZ), a FMOinhibitor, or equimolar concentrations of piperonyl butoxide (PBx), a wellknowngeneral cytochrome P450 (CYP) inhibitor. In both ruminant species,MNPSO2 was the main metabolite detected after MNP incubation with livermicrosomes. The conversion rate of MNP into MNPSO2 was fivefold higher(P < 0.05) in sheep (0.15 0.08 nmol/minmg) compared to cattle. Insheep, the relative involvement of both FMO and CYP systems (FMO/CYP)was 36/64. Virtually, only the CYP system appeared to be involved in theproduction of MNPSO2 in cattle liver. Methimazole significantly reduced (41to 79%) the rate of MNPSO2 production in sheep liver microsomes whereas itdid not inhibit MNP oxidation in cattle liver microsomes. On the other hand,PBx inhibited the production of MNPSO2 in liver microsomes of both sheep(58 to 98%, in a dose-dependent manner) and cattle (almost 100%, independentlyof the PBx concentration added). The incubation of MNP and MNPSO2 with ruminal contents of both species showed a high chemical stability without evident metabolism and/or degradation as well as an extensive degree of adsorption (83% to 90%) to the solid phase of the ruminal content. Overall, these results are a further contribution to the understanding of the metabolicfate of this anthelmintic drug in ruminants.