Assessment of the main metabolic pathways for the flukicidal compound triclabendazole in sheep

VIRKEL G, LIFSCHITZ A, SALLOVITZ J, PIS A, LANUSSE C.

JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS

Blackwell Publishing

Lugar: Londres; Año: 2006 vol. 29 p. 213 - 223

0140-7783

Triclabendazole (TCBZ) is an halogenated benzimidazole (BZD) compoundworldwide used to control immature and adult stages of the liver flukeFasciola hepatica. The purpose of this investigation was to characterize in vitrothe patterns of hepatic and ruminal biotransformation of TCBZ and itsmetabolites in sheep. TCBZ parent drug was metabolized into its sulphoxide(TCBZSO), sulphone (TCBZSO2) and hydroxy derivatives by sheep livermicrosomes. The same microsomal fraction was also able to oxidize TCBZSOinto TCBZSO2 and hydroxy-TCBZSO (HO-TCBZSO). TCBZ sulphoxidation wassignificantly (P < 0.001) inhibited after inactivation of the flavin-monooxygenase(FMO) system (77% inhibition) as well as in the presence of theFMO substrate methimazole (MTZ) (71% inhibition). TCBZ sulphoxidativemetabolism was also reduced (24% inhibition, P < 0.05) by the cytochromeP450 inhibitor piperonyl butoxide (PB). The rate of TCBZSO conversion intoTCBZSO2 was also significantly inhibited by PB (55% inhibition), MTZ (52%inhibition) and also following FMO inactivation (58% inhibition). The datareported here indicate that the FMO is the main enzymatic pathway involvedin TCBZ sulphoxidation (ratio FMO/P450 ¼ 3.83 ± 1.63), although bothenzymatic systems participate in a similar proportion in the sulphonation ofTCBZSO to form the sulphone metabolite (ratio FMO/P450 ¼ 1.31 ± 0.23).Additionally, ketoconazole (KTZ) did not affect TCBZ sulphoxidation butdecreased (66% inhibition, P < 0.05) the formation of TCBZSO2. Similarly,inhibition of TCBZSO2 production was observed after incubation of TCBZSOin the presence of KTZ and erythromycin (ETM). Conversely, thiabendazole(TBZ) and fenbendazole (FBZ) did not affect the oxidative metabolism of bothincubated substrates. The sheep ruminal microflora was able to reduce thesulphoxide (TCBZSO) into the parent thioether (TCBZ). The ruminalsulphoreduction of the HO-TCBZSO derivative into HO-TCBZ was alsodemonstrated. The rate of sulphoreduction of HO-TCBZSO was significantly(P < 0.05) higher than that observed for TCBZSO. The metabolic approachtested here contributes to the identification of the different pathwaysinvolved in drug biotransformation in ruminant species. These findings onthe pattern of hepatic and ruminal biotransformation of TCBZ and its mainmetabolites are a further contribution to the understanding of thepharmacological properties of widely used anthelmintics in ruminants.Comprehension of TCBZ metabolism is critical to optimize its flukicidalactivity.