Abstract
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.
Highlights
Doxazosin (DOX), a long-acting and highly selective α1 receptor blocker, is commonly used in treating benign prostatic hyperplasia (BEH) as the first-line therapy. It can relax the smooth muscle of the prostate and relieve the lower urinary tract symptoms related to BEH by targeting the α1-receptor in the prostate tissue, especially near the bladder neck (Cao et al, 2016; Fusco et al, 2016)
For the identification of metabolites, (±)-DOX was administered to the rats through the caudal vein, and the blood was collected at different time points after administration and analyzed by UHPLC-high-resolution mass spectrometry (HRMS)
To discover more metabolites of DOX, we used the method in vivo in the beginning rather than in vitro because there are many kinds of metabolic enzymes in the body, including carboxylases, dehydrogenases, lipoxygenases, oxidoreductases, kinases, lyases, and transferases (Alexander et al, 2011; Argikar et al, 2016)
Summary
Doxazosin (DOX), a long-acting and highly selective α1 receptor blocker, is commonly used in treating benign prostatic hyperplasia (BEH) as the first-line therapy. It can relax the smooth muscle of the prostate and relieve the lower urinary tract symptoms related to BEH by targeting the α1-receptor in the prostate tissue, especially near the bladder neck (Cao et al, 2016; Fusco et al, 2016). Differences in pharmacological effects between (−)-DOX and (+)-DOX have been reported; that is, the blocking effect of (−)-DOX on α1D receptors in a rat vascular smooth muscle is weaker than that of (+)-DOX They produce opposite inotropic effects in the rat atria, and the chiral carbon atom in the molecular structure of doxazosin does not affect its activity at the therapeutic target of α1A receptors in the rabbit prostate (Zhao et al, 2012). Elucidating the pharmacokinetics of (−)-DOX, (+)-DOX, and (±)-DOX has become an important issue for DOX clinical application
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
