Michiels M, Meuldermans W, Heykants J
Department of Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutica, Beerse, Belgium.
Drug Metab Rev. 1987;18(2-3):235-51. doi: 10.3109/03602538708998307.
Closantel was reasonably well absorbed in sheep and cattle. After oral (10 mg/kg) or parenteral (5 mg/kg) administration, similar peak times (8-48 h) and peak plasma levels (45-55 micrograms/mL) are observed. Plasma level-time curves are superimposable for either route and increase linearly with the dose. The elimination half-life of closantel is 2 to 3 weeks. The relative bioavailability of 50% of oral closantel can partly be explained by incomplete absorption. Experiments in sheep with 14C-closantel revealed that the plasma radioactivity is almost exclusively due to the unmetabolized drug, metabolites accounting for less than 2%. At least 80% of the dose was excreted with the feces over the investigational period of 8 weeks, and less than 0.5% with the urine. Closantel was only poorly metabolized. Over 90% of the fecal radioactivity was due to the parent compound. Two monoiodoclosantel isomers were the only fecal metabolites detected with radio-HPLC. The distribution of closantel to tissues was limited by its high protein binding. Closantel bound strongly (greater than 99.9%) and almost exclusively to plasma albumin. Accordingly, tissue concentrations were many times lower than the corresponding plasma levels. Residual radioactivity in sheep in all tissues but liver was entirely due to closantel. About 30% to 40% of the liver radioactivity could be attributed to monoiodoclosantel. In both sheep and cattle, residual tissue concentrations decline parallel to the plasma concentrations. Consequently, the plasma kinetics of closantel reliably reflect its depletion from tissues. Independently of the dosing scheme and route of administration, the maximum daily intake by the consumer was always below the acceptable daily intake within 4 weeks after the last dose.
氯氰碘柳胺在绵羊和牛体内吸收情况良好。经口服（10毫克/千克）或肠胃外（5毫克/千克）给药后，观察到相似的达峰时间（8 - 48小时）和血浆峰浓度（45 - 55微克/毫升）。两种给药途径的血浆浓度 - 时间曲线可相互叠加，且随剂量呈线性增加。氯氰碘柳胺的消除半衰期为2至3周。口服氯氰碘柳胺的相对生物利用度为50%，部分原因是吸收不完全。用14C - 氯氰碘柳胺对绵羊进行的实验表明，血浆放射性几乎完全源于未代谢的药物，代谢物占比不到2%。在8周的研究期内，至少80%的剂量随粪便排出，随尿液排出的剂量不到0.5%。氯氰碘柳胺代谢程度很低。粪便放射性中超过90%源于母体化合物。用放射性高效液相色谱法检测到的仅有的两种粪便代谢物是单碘氯氰碘柳胺异构体。氯氰碘柳胺在组织中的分布受其高蛋白结合率限制。氯氰碘柳胺与血浆白蛋白紧密结合（大于99.9%）且几乎完全如此。因此，组织浓度比相应的血浆浓度低很多倍。除肝脏外，绵羊所有组织中的残留放射性完全是由氯氰碘柳胺所致。肝脏放射性中约30%至40%可归因于单碘氯氰碘柳胺。在绵羊和牛体内，残留组织浓度均与血浆浓度平行下降。因此，氯氰碘柳胺的血浆动力学能可靠地反映其在组织中的消耗情况。无论给药方案和给药途径如何，消费者的最大日摄入量在末次给药后4周内始终低于可接受的每日摄入量。
