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Bama Miniature Pigs (Sus scrofa domestica) as a Model for Drug Evaluation for Humans: Comparison of In Vitro Metabolism and In Vivo Pharmacokinetics of Lovastatin

机译:巴马小型猪(Sus scrofa domestica)作为人类药物评估的模型:洛伐他汀的体外代谢和体内药代动力学比较

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The objective of this study was to demonstrate that Bama miniature pigs are a suitable experimental animal model for the evaluation of drugs for man. To this end, in vitro lovastatin metabolism at the minipig liver microsomal level and in vivo pharmacokinetics were studied. Results were compared with those obtained from humans. Our data indicate that the main metabolites and enzyme kinetic parameters of lovastatin metabolism are similar in pigs and humans. Triacetyloleandomycin, a specific inhibitor of human CYP3A4, inhibited the metabolism of lovastatin in pig and human liver microsomes. In addition, the pharmacokinetic parameters and absolute bioavailability suggested that the absorption and elimination of lovastatin in Bama miniature pigs were similar to those in humans. Lovastatin was distributed across many organs in pigs, but the highest levels were found in the stomach, intestines, and liver. Within 96 h, 7% and 82% of the given dose was excreted in the urine and feces, respectively. In addition, no significant species differences in the plasma protein binding ratio of lovastatin and the rates of lovastatin hydrolysis to beta-hydroxyacid lovastatin were apparent. From these results, we conclude that Bama miniature pigs are suitable for use in drug evaluation studies.
机译:这项研究的目的是证明巴马小型猪是用于评估人类药物的合适实验动物模型。为此,研究了小猪肝脏微粒体水平的体外洛伐他汀代谢和体内药代动力学。将结果与从人类获得的结果进行比较。我们的数据表明,洛伐他汀的主要代谢产物和酶动力学参数在猪和人中相似。 Triacetoleandomycin,一种人CYP3A4的特异性抑制剂,抑制洛伐他汀在猪和人肝微粒体内的代谢。此外,药代动力学参数和绝对生物利用度表明,巴马小型猪对洛伐他汀的吸收和消除与人相似。洛伐他汀分布在猪的许多器官中,但在胃,肠和肝中含量最高。在96小时内,给定剂量的7%和82%分别从尿液和粪便中排出。另外,在洛伐他汀的血浆蛋白结合率和洛伐他汀水解为β-羟酸洛伐他汀的速率上没有明显的物种差异。根据这些结果,我们得出结论,巴马小型猪适合用于药物评估研究。

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