说明Maribavir代谢和处置途径的非人灵长类动物通过质量平衡和Semi-Physiologically建模方法。

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太阳K, Welty D

说明Maribavir代谢和处置途径的非人灵长类动物通过质量平衡和Semi-Physiologically建模方法。

药物金属底座Dispos。2021年11月,49 (11):1025 - 1037。doi: 10.1124 / dmd.121.000493。Epub 2021年8月30日。

PubMed ID

34462268 (在PubMed

]

文摘

Maribavir的3期临床开发治疗巨细胞病毒感染/疾病在移植受者。先前的研究只使用完整的必威国际app猕猴表示胆汁分泌的主要消除途径maribavir maribavir经历肝肠循环(EHR)。澄清maribavir EHR的行为的确切机制,我们研究了间隙通道使用静脉注射(14)C-labeled maribavir完整和胆汁duct-cannulated (BDC)猴子和构造一个基于semi-physiologically药代动力学(PBPK)模型。总放射性代谢物概要文件在等离子体和排泄物,以及测定其血浆maribavir浓度。完整的动物显示显著降低间隙和更长的半衰期在总辐射和父母在等离子体浓度比BDC猴子。主要在体外和体内代谢途径在猴子直接glucuronidation maribavir;N-dealkylation和肾清除率是次要的途径。在BDC猴子,73%的剂量是恢复maribavir葡糖苷酸在胆汁,和3%的剂量在胆汁和粪便被恢复为父;在完整的动物的粪便,58%的剂量是恢复作为家长,和未发现葡糖苷酸。因此,EHR maribavir发生通过胆汁的分泌maribavir葡糖苷酸,这是紧随其后的是水解葡糖苷酸在肠道内腔和随后的再吸收的父母。 A semi-PBPK model constructed from physiologic, in vitro, and in vivo BDC monkey data is capable of projecting maribavir's pharmacokinetic and EHR behavior in intact animals after intravenous or oral dosing and could be applied to modeling other xenobiotics that are subject to similar EHR processes. SIGNIFICANCE STATEMENT: Through both mass balance and semi-physiologically based pharmacokinetic (semi-PBPK) modeling approaches, this study mechanistically and quantitatively elucidates maribavir's enterohepatic recirculation (EHR) behavior in monkeys, which occurs via extensive direct glucuronidation, biliary secretion of these glucuronides, luminal hydrolysis of glucuronides to parent, and subsequent reabsorption of the parent. The study also identifies important drug- and animal-specific parameters that determine the EHR kinetics, and the semi-PBPK model is readily applicable to other drugs that undergo similar metabolic and recirculation mechanisms.

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药物

Maribavir