The metabolism of the orexin-1 selective receptor antagonist nivasorexant.

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY
Alexander Treiber, Swen Seeland, Belal Haschimi, Aude Weigel, Jodi T Williams, Jerome Gabillet
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引用次数: 0

Abstract

Nivasorexant was the first orexin-1 selective receptor antagonist entering clinical development. Despite encouraging preclinical evidence in animal models, a proof-of-concept trial in binge-eating patients recently failed to demonstrate its clinical utility in this population.Across species, nivasorexant clearance was driven by metabolism along seven distinct pathways, five of which were hydroxylation reactions in various locations of the molecule. The exact sites of metabolism were identified by means of mass spectrometry, the use of deuterated analogues, and finally confirmed by chemical references.CYP3A4 was the main cytochrome P450 enzyme involved in nivasorexant metabolism in vitro and accounting for about 90% of turnover in liver microsomes. Minor roles were taken by CYP2C9 and CYP2C19 but individually did not exceed 3-7%.In the rat, nivasorexant was mostly excreted via the bile after extensive metabolism, while urinary excretion was negligible. Only traces of the parent drug were detected in urine, bile, or faeces.

俄勒欣-1 选择性受体拮抗剂 Nivasorexant 的新陈代谢
1.Nivasorexant 是第一种进入临床开发阶段的奥曲肽-1 选择性受体拮抗剂。尽管动物模型的临床前证据令人鼓舞,但最近在暴食患者中进行的概念验证试验未能证明它在这一人群中的临床效用。 在不同物种中,nivasorexant 的清除是由七种不同途径的代谢驱动的,其中五种是分子不同位置的羟化反应。CYP3A4 是参与尼伐沙星体外代谢的主要细胞色素 P450 酶,约占肝脏微粒体代谢的 90%。CYP2C9 和 CYP2C19 发挥次要作用,但各自的作用不超过 3-7%。在大鼠体内,nivasorexant 经过大量代谢后,大部分通过胆汁排出体外,而尿液中的排泄量几乎可以忽略不计。在尿液、胆汁或粪便中只能检测到微量的母体药物。
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来源期刊
Xenobiotica
Xenobiotica 医学-毒理学
CiteScore
3.80
自引率
5.60%
发文量
96
审稿时长
2 months
期刊介绍: Xenobiotica covers seven main areas, including:General Xenobiochemistry, including in vitro studies concerned with the metabolism, disposition and excretion of drugs, and other xenobiotics, as well as the structure, function and regulation of associated enzymesClinical Pharmacokinetics and Metabolism, covering the pharmacokinetics and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in manAnimal Pharmacokinetics and Metabolism, covering the pharmacokinetics, and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in animalsPharmacogenetics, defined as the identification and functional characterisation of polymorphic genes that encode xenobiotic metabolising enzymes and transporters that may result in altered enzymatic, cellular and clinical responses to xenobioticsMolecular Toxicology, concerning the mechanisms of toxicity and the study of toxicology of xenobiotics at the molecular levelXenobiotic Transporters, concerned with all aspects of the carrier proteins involved in the movement of xenobiotics into and out of cells, and their impact on pharmacokinetic behaviour in animals and manTopics in Xenobiochemistry, in the form of reviews and commentaries are primarily intended to be a critical analysis of the issue, wherein the author offers opinions on the relevance of data or of a particular experimental approach or methodology
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