The kinetics of triclabendazole disposition in sheep

Abstract

To investigate whether the disposition of triclabendazole (TCBZ) and its metabolites in blood or bile influenced its flukicidal potency, TCBZ was administered intraruminally at 10 mg kg-1 to sheep surgically fitted with a permanent re-entrant bile duct cannula. The profiles of TCBZ metabolites in peripheral plasma and bile were determined using high performance liquid chromatography. In plasma, only TCBZ sulphoxide (TCBZ-SO) and TCBZ sulphone were present and reached their maximum concentrations (greater than 13 micrograms ml-1) at 18 and 36 h, respectively, after administration. TCBZ metabolites were specifically bound to plasma albumin, which is believed to exert a major influence on the duration of plasma TCBZ metabolite concentrations and consequent exposure of liver fluke. In bile, the major TCBZ metabolites were hydroxylated in the 4' position and secreted predominantly as sulphate esters with lesser proportions as glucuronide conjugates. The major biliary metabolite was conjugated hydroxy TCBZ-SO which reached a maximum concentration in excess of 40 micrograms ml-1 and contributed almost half the total conjugated metabolites. The major free biliary metabolite was TCBZ-SO. Of the administered TCBZ dose, 9.7% was secreted as free metabolites in bile whereas 35.8% was secreted as conjugated metabolites. Approximately 6.5% of the dose was excreted in urine.

The comparative metabolism of triclabendazole sulphoxide by triclabendazole-susceptible and triclabendazole-resistant Fasciola hepatica

“…A concentration of 50 lg/ml is equivalent to that used in previous studies using TCBZ-SO against F. hepatica Fairweather 1993, 1994;Robinson et al 2002) and was chosen so that comparisons with this body of data could be made. However, this concentration is considerably higher than that to which flukes are exposed in vivo: the peak plasma concentration reached in sheep is 13.3 lg/ml, within which flukes are exposed to levels greater than 10 lg/ml for approximately 18 h (Hennessy et al 1987). Over the 3-12 h time period, the mean concentration of TCBZ-SO within TCBZ-susceptible flukes was 0.051 mM, whereas in the TCBZ-resistant flukes the mean concentration was 0.082 mM.…”

“…The latter approach was used to preserve the compartmentalisation of the liver fluke cells and to allow the operation of intact excretory systems. TCBZ-SO was chosen in preference to TCBZ to mirror more accurately the situation in vivo, as flukes are mainly exposed to TCBZ-SO due to extensive sulphoxidation of the parent compound by the host animal (Hennessy et al 1987). …”

“…Parent BZM compounds, including TCBZ, are extensively metabolised to their sulphoxide metabolites by the host animal (Hennessy et al 1987;Alvarez et al 2000); therefore the parasites are primarily exposed to the sulphoxide metabolite. TCBZ-SO is believed to be the most active form of the drug: efficacy trials have shown that TCBZ-SO, when administered to infected sheep as a drench (10 mg/kg), reduced fluke counts by 100% (Bu¨scher et al 1999).…”

Determination of Triclabendazole in Cattle Plasma as Its Sulphoxide and Sulphone Metabolites by Rotating Disk Sorptive Extraction Combined With High-Performance Liquid Chromatography and Its Application to Pharmacokinetic Studies

“…Despite its activity, TCB is practically absent in plasma, however, after distribution, its active metabolite TCB-SO is the responsible of the fasciolicide activity; meanwhile TCB-SO2 is an inactive metabolite that accounts for the drug elimination stage. 2,3 The antiparasitic activity of the TCB is time dependent. Its therapeutic effects occur when the administered product maintains effective concentrations of TCB and TCB-SO at the location of Fasciola hepatica.…”

Erratum to: Inhibition of triclabendazole metabolism in vitro by ketoconazole increases disruption to the tegument of a triclabendazole-resistant isolate of Fasciola hepatica

“…SO used correspond to the maximum blood level of TCBZ. SO reached in vivo (13.3 μg/ml following a therapeutic dose of 10 mg/kg TCBZ in sheep; Hennessy et al 1987). Controls were prepared by incubating whole flukes in NCTC 135 medium for 24 h at 37°C.…”