BILIARY-SECRETION AND ENTEROHEPATIC RECYCLING OF FENBENDAZOLE METABOLITES IN SHEEP
BILIARY-SECRETION AND ENTEROHEPATIC RECYCLING OF FENBENDAZOLE METABOLITES IN SHEEP
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DOI：
10.1111/j.1365-2885.1993.tb00157.x
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发表时间：
1993-06-01
影响因子：
1.3
通讯作者：
PRICHARD, RK
中科院分区：
文献类型：
--
作者：
HENNESSY, DR;STEEL, JW;PRICHARD, RK
在装有永久性胆管插管的绵羊体内注射芬苯达唑(FBZ)，剂量为5.0 mg/kg，含有微量的[C-14]-FBZ，并检测FBZ及其代谢物在胆汁和血浆中的行为。在给药的放射性标记剂量中，47%是在胆汁中分泌的，其中34%是结合态，4%是非结合态(游离)代谢物。羟基恶芬达唑(OH.OFZ)是主要的胆汁代谢物，占总代谢物的66%，羟基FBZ(OH.FBZ)占27%。少量的OFZ和羟基FBZ Selone(OH.FBZ.SO2)也存在于胆汁中。OH.OFZ在胆汁中的迅速出现，甚至在血浆中OFZ的最大浓度出现之前，表明FBZ的主要代谢途径是硫氧化和羟化。随着游离胆汁代谢物的十二指肠内输注，FBZ及其代谢物在胆汁中迅速出现，表明FBZ从小肠吸收。当输注结合代谢物时，它们在停止输注后继续在胆汁中出现15-20小时，这表明羟化代谢物的吸收主要发生在大肠细菌去结合后。据估计，大约40%的胆汁代谢物发生了肠-肝重吸收，但它们对血浆中的代谢物含量的贡献很小。提示在再循环过程中，胆汁代谢产物与小肠和大肠粘膜中的寄生虫有实质性接触，从而有助于FBZ的驱虫活性。
Fenbendazole (FBZ) was administered intraruminally at 5.0 mg/kg, containing a trace of [C-14]-FBZ, to sheep fitted with a permanent bile duct cannula and the behaviour of FBZ and its metabolites examined in bile and plasma. Of the administered radiolabelled dose, 47% was secreted in bile of which 34% was accounted for as conjugated and 4% as unconjugated (free) metabolites. Hydroxylated oxfendazole (OH.OFZ) was the major biliary metabolite contributing 66%, and hydroxy-FBZ (OH.FBZ) 27%, of the total metabolites characterized. Small amounts of OFZ and hydroxy FBZ sulphone (OH. FBZ.SO2) were also present in bile. The rapid appearance of OH.OFZ in bile, even before maximum concentrations of OFZ occurred in plasma, indicated that sulphoxidation and hydroxylation was the major route of FBZ metabolism.Following intraduodenal infusion of free biliary metabolites, FBZ and its metabolites rapidly appeared in bile indicating absorption from the small intestine. When conjugated metabolites were infused they continued to appear in bile for a further 15-20 h after cessation of infusion indicating that absorption of hydroxylated metabolites occurred largely after bacterial deconjugation in the large intestine. Approximately 40% of biliary metabolites were estimated to undergo enterohepatic reabsorption but they contributed minimally to the metabolite content in plasma. It is suggested that during the process of recycling, biliary metabolites make substantial contact with parasites in the mucosa of the small and large intestine thereby contributing to the anthelmintic activity of FBZ.