Elucidating a Complicated Enantioselective Metabolic Profile: A Study From Rats to Humans Using Optically Pure Doxazosin.
Elucidating a Complicated Enantioselective Metabolic Profile: A Study From Rats to Humans Using Optically Pure Doxazosin.
复制标题
阐明复杂的对映选择性代谢特征：使用光学纯多沙唑嗪从大鼠到人类的研究
DOI：
10.3389/fphar.2022.834897
复制
发表时间：
2022
影响因子：
5.6
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Kong D;Tian Y;Duan K;Guo W;Zhang Q;Zhang P;Yang Z;Qin X;Ren L;Zhang W
多沙唑嗪（DOX）是一种外消旋药物，临床用于治疗良性前列腺增生和高血压。近年来研究发现，DOX的两种对映体在血药浓度和药理作用方面存在差异。然而，DOX的立体选择性代谢特征和机制尚不清楚。在此，我们根据我们全面有效的策略鉴定了34种DOX在大鼠中的代谢产物。使用最先进的多元统计方法，根据动力学参数分析了（-）-DOX和（+）-DOX给药之间代谢物和最具区别性的代谢物之间的关系。为了阐明体内和体外的对映体选择性代谢特征，我们仔细研究了大鼠血浆、大鼠肝微粒体（RLM）或人肝微粒体（HLM）和重组人细胞色素P450（CYP）酶中光学纯异构体给药后代谢物的代谢特征。因此，基于这些代谢物的暴露和消除速率，发现这些代谢物的差异，并且（±）-DOX的代谢谱与（+）-DOX的代谢谱更相似。尽管在RLM和HLM中鉴别的代谢物相同，但（−）-DOX和（+）-DOX的代谢物代谢谱差异很大。此外，四种人源性β-内酰胺酶都可以催化DOX产生代谢产物，但它们的选择性似乎不同。例如，CYP 3A 4高度特异性和选择性地催化（−）-DOX形成特定代谢物（M22）。总之，我们建立了一个完整的代谢体系，使用纯光学异构体从体内到体外，和复杂的对映体选择性的代谢产物的DOX清楚地显示。更重要的是，综合代谢系统也适合研究其他手性药物。
Doxazosin (DOX) is prescribed as a racemic drug for the clinical treatment of benign prostatic hyperplasia and hypertension. Recent studies found that the two enantiomers of DOX exhibit differences in blood concentration and pharmacological effects. However, the stereoselective metabolic characteristics and mechanisms for DOX are not yet clear. Herein, we identified 34 metabolites of DOX in rats based on our comprehensive and effective strategy. The relationship among the metabolites and the most discriminative metabolites between (−)-DOX and (+)-DOX administration was analyzed according to the kinetic parameters using state-of-the-art multivariate statistical methods. To elucidate the enantioselective metabolic profile in vivo and in vitro, we carefully investigated the metabolic characteristics of metabolites after optically pure isomers administration in rat plasma, rat liver microsomes (RLMs) or human liver microsomes (HLMs), and recombinant human cytochrome P450 (CYP) enzymes. As a result, the differences of these metabolites were found based on their exposure and elimination rate, and the metabolic profile of (±)-DOX was more similar to that of (+)-DOX. Though the metabolites identified in RLMs and HLMs were the same, the metabolic profiles of the metabolites from (−)-DOX and (+)-DOX were greatly different. Furthermore, four human CYP enzymes could catalyze DOX to produce metabolites, but their preferences seemed different. For example, CYP3A4 highly specifically and selectively catalyzed the formation of the specific metabolite (M22) from (−)-DOX. In conclusion, we established a comprehensive metabolic system using pure optical isomers from in vivo to in vitro, and the complicated enantioselectivity of the metabolites of DOX was clearly shown. More importantly, the comprehensive metabolic system is also suitable to investigate other chiral drugs.
登录
查看更多内容
DOI：
10.1016/j.jpba.2015.11.023
发表时间：
2016-02-05
影响因子：
3.4
作者：
Kim, Ju Hyun;Kim, Hee Seung;Lee, Hye Suk
通讯作者：
Lee, Hye Suk
影响因子：
6.1
作者：
Macherius, Andre;Seiwert, Bettina;Reemtsma, Thorsten
通讯作者：
Reemtsma, Thorsten
影响因子：
4.6
作者：
Kong, Dezhi;Li, Qing;Ren, Leiming
通讯作者：
Ren, Leiming
一项随机的，开放标签的，对良性前列腺增生症患者的甲状腺素和toLterosin和doxazosin结合的疗效和安全性的比较研究。
DOI：
10.12659/msm.896283
发表时间：
2016-06-04
期刊：
Medical science monitor : international medical journal of experimental and clinical research
影响因子：
--
作者：
Cao Y;Wang Y;Guo L;Yang X;Chen T;Niu H
通讯作者：
Niu H
影响因子：
9.8
作者：
Bujak, Ivana Tartaro;Kralj, Mojca Bavcon;Trebse, Polonca
通讯作者：
Trebse, Polonca