新型Kappa阿片受体激动剂[14C]HSK21542在人体内的药代动力学、质量平衡和代谢。

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Jin-Jie Yuan, Yi-Cong Bian, Sheng Ma, Wei Chen, Feng-Yi Zhang, Hua Zhang, Li-Yan Miao
{"title":"新型Kappa阿片受体激动剂[14C]HSK21542在人体内的药代动力学、质量平衡和代谢。","authors":"Jin-Jie Yuan, Yi-Cong Bian, Sheng Ma, Wei Chen, Feng-Yi Zhang, Hua Zhang, Li-Yan Miao","doi":"10.1007/s13318-023-00858-0","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objective: </strong>HSK21542, a synthetic short-chain polypeptide, is a selective peripheral kappa opioid receptor (KOR) agonist. In this single-centre, non-randomized, open-label study, the pharmacokinetics, mass balance, metabolism and excretion of HSK21542 were investigated.</p><p><strong>Methods: </strong>A single intravenous dose of 2 μg/0.212 μCi/kg [<sup>14</sup>C]HSK21542 was administered to six healthy male subjects. Samples of blood, urine and faeces were collected for quantitative determination of total radioactivity and unchanged HSK21542, and identification of metabolites.</p><p><strong>Results: </strong>The mean total recovery was 81.89% of the radiolabelled dose over 240 h post-dose, with 35.60% and 46.30% excreted in faeces and urine, respectively. The mean maximum concentration (C<sub>max</sub>), the half-life (t<sub>1/2</sub>) and the area under the concentration-time curve (AUC<sub>0-t</sub>) of total radioactivity (TRA) in plasma were 20.4 ±4.16 ng Eq./g, 1.93 ± 0.322 h and 21.8 ± 2.93 h·ng Eq./g, respectively, while the C<sub>max</sub>, t<sub>1/2</sub> and the AUC<sub>0-t</sub> of unchanged HSK21542 were 18.3 ± 3.36 ng/mL, 1.66 ± 0.185 h and 18.4 ± 2.24 h·ng/mL, respectively. The blood-to-plasma ratios of TRA at several times ranged from 0.46 to 0.54. [<sup>14</sup>C]HSK21542 was detected as the main circulating substance in plasma, accounting for 92.17% of the AUC of TRA. The unchanged parent compound was the only major radioactive chemical in urine (100.00% of TRA) and faeces (93.53% of TRA). Metabolites were very minor components.</p><p><strong>Conclusions: </strong>HSK21542 was barely metabolized in vivo and mainly excreted with unchanged HSK21542 as its main circulating component in plasma. It was speculated that renal excretion was the principal excretion pathway, and faecal excretion was the secondary pathway.</p><p><strong>Clinical trial registration number: </strong>NCT05835934.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9000,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pharmacokinetics, Mass Balance and Metabolism of [<sup>14</sup>C]HSK21542, a Novel Kappa Opioid Receptor Agonist, in Humans.\",\"authors\":\"Jin-Jie Yuan, Yi-Cong Bian, Sheng Ma, Wei Chen, Feng-Yi Zhang, Hua Zhang, Li-Yan Miao\",\"doi\":\"10.1007/s13318-023-00858-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objective: </strong>HSK21542, a synthetic short-chain polypeptide, is a selective peripheral kappa opioid receptor (KOR) agonist. In this single-centre, non-randomized, open-label study, the pharmacokinetics, mass balance, metabolism and excretion of HSK21542 were investigated.</p><p><strong>Methods: </strong>A single intravenous dose of 2 μg/0.212 μCi/kg [<sup>14</sup>C]HSK21542 was administered to six healthy male subjects. Samples of blood, urine and faeces were collected for quantitative determination of total radioactivity and unchanged HSK21542, and identification of metabolites.</p><p><strong>Results: </strong>The mean total recovery was 81.89% of the radiolabelled dose over 240 h post-dose, with 35.60% and 46.30% excreted in faeces and urine, respectively. The mean maximum concentration (C<sub>max</sub>), the half-life (t<sub>1/2</sub>) and the area under the concentration-time curve (AUC<sub>0-t</sub>) of total radioactivity (TRA) in plasma were 20.4 ±4.16 ng Eq./g, 1.93 ± 0.322 h and 21.8 ± 2.93 h·ng Eq./g, respectively, while the C<sub>max</sub>, t<sub>1/2</sub> and the AUC<sub>0-t</sub> of unchanged HSK21542 were 18.3 ± 3.36 ng/mL, 1.66 ± 0.185 h and 18.4 ± 2.24 h·ng/mL, respectively. The blood-to-plasma ratios of TRA at several times ranged from 0.46 to 0.54. [<sup>14</sup>C]HSK21542 was detected as the main circulating substance in plasma, accounting for 92.17% of the AUC of TRA. The unchanged parent compound was the only major radioactive chemical in urine (100.00% of TRA) and faeces (93.53% of TRA). Metabolites were very minor components.</p><p><strong>Conclusions: </strong>HSK21542 was barely metabolized in vivo and mainly excreted with unchanged HSK21542 as its main circulating component in plasma. It was speculated that renal excretion was the principal excretion pathway, and faecal excretion was the secondary pathway.</p><p><strong>Clinical trial registration number: </strong>NCT05835934.</p>\",\"PeriodicalId\":11939,\"journal\":{\"name\":\"European Journal of Drug Metabolism and Pharmacokinetics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.9000,\"publicationDate\":\"2023-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Journal of Drug Metabolism and Pharmacokinetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s13318-023-00858-0\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/10/13 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Drug Metabolism and Pharmacokinetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s13318-023-00858-0","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/10/13 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

摘要

背景与目的:HSK21542是一种合成的短链多肽,是一种选择性外周κ阿片受体激动剂。在这项单中心、非随机、开放标签研究中,研究了HSK21542的药代动力学、质量平衡、代谢和排泄。方法:6名健康男性受试者单次静脉注射2μg/0.212μCi/kg[14C]HSK21542。采集血液、尿液和粪便样本,用于定量测定总放射性和不变的HSK21542,并鉴定代谢物。结果:在给药后240小时内,平均总回收率为放射性标记剂量的81.89%,其中35.60%和46.30%分别通过粪便和尿液排出。血浆中总放射性(TRA)的平均最大浓度(Cmax)、半衰期(t1/2)和浓度-时间曲线下面积(AUC0-t)分别为20.4±4.16 ng Eq./g、1.93±0.322 h和21.8±2.93 h·ng Eq./g,而不变的HSK21542的Cmax、t1/2和AUC0-t分别为18.3±3.36 ng/mL、1.66±0.185 h和18.4±2.24 h·ng/mL,分别地TRA的血浆比在几个时间范围内为0.46至0.54。[14C]HSK21542为血浆中主要循环物质,占TRA AUC的92.17%。不变的母体化合物是尿液(占TRA的100.00%)和粪便(占TRA的93.53%)中唯一的主要放射性化学物质。代谢物是非常次要的成分。结论:HSK21542在体内几乎没有代谢,主要以血浆中HSK21542-为主要循环成分而排泄。推测肾脏排泄是主要排泄途径,粪便排泄是次要排泄途径。临床试验注册号:NCT05835934。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Pharmacokinetics, Mass Balance and Metabolism of [<sup>14</sup>C]HSK21542, a Novel Kappa Opioid Receptor Agonist, in Humans.

Pharmacokinetics, Mass Balance and Metabolism of [14C]HSK21542, a Novel Kappa Opioid Receptor Agonist, in Humans.

Background and objective: HSK21542, a synthetic short-chain polypeptide, is a selective peripheral kappa opioid receptor (KOR) agonist. In this single-centre, non-randomized, open-label study, the pharmacokinetics, mass balance, metabolism and excretion of HSK21542 were investigated.

Methods: A single intravenous dose of 2 μg/0.212 μCi/kg [14C]HSK21542 was administered to six healthy male subjects. Samples of blood, urine and faeces were collected for quantitative determination of total radioactivity and unchanged HSK21542, and identification of metabolites.

Results: The mean total recovery was 81.89% of the radiolabelled dose over 240 h post-dose, with 35.60% and 46.30% excreted in faeces and urine, respectively. The mean maximum concentration (Cmax), the half-life (t1/2) and the area under the concentration-time curve (AUC0-t) of total radioactivity (TRA) in plasma were 20.4 ±4.16 ng Eq./g, 1.93 ± 0.322 h and 21.8 ± 2.93 h·ng Eq./g, respectively, while the Cmax, t1/2 and the AUC0-t of unchanged HSK21542 were 18.3 ± 3.36 ng/mL, 1.66 ± 0.185 h and 18.4 ± 2.24 h·ng/mL, respectively. The blood-to-plasma ratios of TRA at several times ranged from 0.46 to 0.54. [14C]HSK21542 was detected as the main circulating substance in plasma, accounting for 92.17% of the AUC of TRA. The unchanged parent compound was the only major radioactive chemical in urine (100.00% of TRA) and faeces (93.53% of TRA). Metabolites were very minor components.

Conclusions: HSK21542 was barely metabolized in vivo and mainly excreted with unchanged HSK21542 as its main circulating component in plasma. It was speculated that renal excretion was the principal excretion pathway, and faecal excretion was the secondary pathway.

Clinical trial registration number: NCT05835934.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
3.70
自引率
0.00%
发文量
64
审稿时长
>12 weeks
期刊介绍: Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信