AUTHOR=Kong Dezhi , Tian Yuan , Duan Kunfeng , Guo Wenyan , Zhang Qingning , Zhang Panpan , Yang Zuxiao , Qin Xia , Ren Leiming , Zhang Wei 

TITLE=Elucidating a Complicated Enantioselective Metabolic Profile: A Study From Rats to Humans Using Optically Pure Doxazosin

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.834897

DOI=10.3389/fphar.2022.834897

ISSN=1663-9812

ABSTRACT=Doxazosin (DOX) prescribed as a racemic drug for clinical treatment of benign prostatic hyperplasia and hypertension. Recent researches found the two enantiomers of DOX exhibit the differences in blood concentration and in pharmacological effects. However, the stereoselective metabolic characteristics and mechanisms for DOX are not yet clear. Here 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, in rat liver microsomes (RLMs) or human liver microsomes (HLMs), and in 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 great different. Furthermore, four human CYP enzymes could catalyze DOX to produce metabolites, but their preferences seemed to be different, e.g., 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.