Laboratorio de Farmacología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires y Centro de Investigación Veterinaria de Tandil (CIVETAN), CONICET, Tandil, Argentina.
Laboratorio de Farmacología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires y Centro de Investigación Veterinaria de Tandil (CIVETAN), CONICET, Tandil, Argentina.
Exp Parasitol. 2014 Jan;136:14-9. doi: 10.1016/j.exppara.2013.10.014. Epub 2013 Nov 7.
The flukicidal compound triclabendazole (TCBZ) has a complex metabolic pattern that includes the systemic presence of its sulphoxide (TCBZ.SO) and sulphone (TCBZ.SO2) metabolites, usually recovered from the bile of treated animals. The aim of the current work was to evaluate the time-course and pattern of in vivo accumulation of TCBZ/metabolites into adult Fasciola hepatica specimens recovered from infected sheep. Twelve (12) healthy Corriedale sheep were orally infected with one hundred (100) metacercariae of the TCBZ-susceptible Cullomptom isolate of F. hepatica. Sixteen weeks after infection, animals were intraruminally treated with TCBZ (10mg/kg). At 3, 24, 48 and 60h post-treatment (pt), animals were sacrificed (n=3/time period) and samples of blood, bile, liver tissue and adult F. hepatica specimens were collected. The concentrations of TCBZ/metabolites were measured by HPLC. TCBZ.SO and TCBZ.SO2 were the only molecules recovered in the bloodstream, with peak plasma concentrations of 10.8μg/mL (TCBZ.SO) and 12.6μg/mL (TCBZ.SO2). The same metabolites were also the main analytes accumulated within the adult flukes, reaching peak concentrations between 6.35μg/g (TCBZ.SO) and 13.9μg/g (TCBZ.SO2) at 24h pt, which was coincident with the time when the maximum plasma concentration was attained. Low levels of TCBZ parent drug (0.14μg/g at 24h pt) were measured within collected flukes. TCBZ parent drug and its sulpho- and hydroxy-derivatives were recovered in bile collected from treated sheep between 3 and 60h pt. Although relatively high concentrations of hydroxy-TCBZ (ranging from 0.86 to 10.1μg/mL) were measured in bile, this metabolite was not recovered within the flukes at any time pt. Finally, TCBZ parent drug was the main compound accumulated in liver tissue over the 60h pt period. The time-course and drug concentration patterns within the adult liver fluke after TCBZ treatment followed a similar trend to those observed in plasma. Overall, the data reported here confirm that oral ingestion is a main route of drug entry into the trematode in vivo exposed to TCBZ/metabolites. However, the presence of TCBZ within the adult fluke (despite being absent in the systemic circulation) may be related to some degree of trans-tegumental diffusion from bile or by a direct oral ingestion from portal blood.
氟苯达唑（TCBZ）是一种杀肝片吸虫化合物，其代谢模式复杂，包括其亚砜（TCBZ.SO）和砜（TCBZ.SO2）代谢物在体内的系统存在，通常从治疗动物的胆汁中回收。本研究旨在评估在感染绵羊中回收的成虫肝片吸虫标本中 TCBZ/代谢物的体内积累时间过程和模式。12 只健康的科里代尔绵羊经口感染了 100 个对 TCBZ 敏感的 Cullomptom 分离株的肝片形吸虫囊蚴。感染后 16 周，动物经瘤胃内给予 TCBZ（10mg/kg）。在治疗后 3、24、48 和 60 小时（pt），处死动物（n=3/时间点）并收集血液、胆汁、肝组织和成虫肝片吸虫标本。采用高效液相色谱法测定 TCBZ/代谢物的浓度。TCBZ.SO 和 TCBZ.SO2 是唯一在血液中回收的分子，其血浆峰浓度分别为 10.8μg/mL（TCBZ.SO）和 12.6μg/mL（TCBZ.SO2）。同一代谢物也是成虫吸虫中主要积累的分析物，在 24h pt 时达到 6.35μg/g（TCBZ.SO）和 13.9μg/g（TCBZ.SO2）的峰值浓度，这与达到最大血浆浓度的时间一致。在收集的吸虫中仅测量到 TCBZ 母体药物的低水平（24h pt 时为 0.14μg/g）。在治疗绵羊的胆汁中，3 至 60h pt 期间回收了 TCBZ 母体药物及其亚砜和羟基衍生物。尽管在胆汁中测量到相对较高浓度的羟基 TCBZ（范围为 0.86 至 10.1μg/mL），但在任何时间点 pt 均未在吸虫中回收该代谢物。最后，在 60h pt 期间，TCBZ 母体药物是肝组织中主要积累的化合物。在 TCBZ 处理后，成虫肝吸虫内的时间过程和药物浓度模式与在血浆中观察到的相似。总的来说，这里报道的数据证实，口服摄入是体内暴露于 TCBZ/代谢物的吸虫进入药物的主要途径。然而，尽管成虫吸虫中不存在 TCBZ（尽管在系统循环中不存在），但它可能与从胆汁中某种程度的跨体扩散或直接从门静脉血中的口服摄入有关。
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