Pharmacokinetics and multi-peak phenomenon analysis of novel anti-Parkinson's drug FLZ after multi-dose in cynomolgus monkeys.

IF 1.3 4区医学 Q4 PHARMACOLOGY & PHARMACY

Xenobiotica Pub Date : 2024-04-01 Epub Date: 2024-04-17 DOI:10.1080/00498254.2024.2326475

Jiayu Li, Shuofeng Zhang, Rui Chen

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Abstract

The novel anti-Parkinson disease drug, FLZ, had a complicated drug absorption and metabolise process reported in single-dose studies. A multi-peak absorption peak phenomenon was found.This study focused on the multi-dose pharmacokinetics (PK) characteristics of FLZ, T1, and T2 in cynomolgus monkeys and raised discussion on its multi-peak absorption situation. Different doses of FLZ ranging from 75 to 300 mg/kg were administered orally to 16 cynomolgus monkeys. The whole treatment period lasted for 42 days with FLZ once a day.The primary metabolites of FLZ were Target1 (T1) and Target2 (T2), which had plasma exposure (calculated as AUC_0-24, day 42) approximately 2 and 10 times higher than the parent drug. The proportion of plasma exposure increase was lower than the proportion of dose increase in FLZ, T1, and T2.Gender influenced its exposure (AUC_0-24) with approximately 3-fold higher in males than females. There was no significant accumulation of T1 and T2. Enterohepatic Circulation (EHC) and gastrointestinal (GI) tract absorption may be involved in the mechanism of multi-peak characteristics.

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新型抗帕金森氏症药物 FLZ 在绒猴体内多次给药后的药代动力学和多峰现象分析

据报道，新型抗帕金森病药物FLZ在单剂量研究中存在复杂的药物吸收和代谢过程。本研究重点研究了FLZ、T1和T2在猴体内的多剂量药代动力学（PK）特征，并对其多峰吸收情况进行了讨论。16只猴口服了不同剂量的FLZ，剂量从75毫克/千克到300毫克/千克不等。FLZ的主要代谢产物为Target1（T1）和Target2（T2），它们的血浆暴露量（以AUC0-24计算，第42天）比母药分别高出约2倍和10倍。FLZ、T1和T2的血浆暴露量增加比例低于剂量增加比例。性别影响其暴露量（AUC0-24），男性比女性高约3倍。T1和T2没有明显的蓄积现象。肝内循环（EHC）和胃肠道吸收可能参与了多峰特征的形成机制。

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来源期刊

Xenobiotica 医学-毒理学

CiteScore

3.80

自引率

5.60%

发文量

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