The truth about the lower plasma concentration of the (-)-isomer after racemic doxazosin administration in rats: Stereoselective inhibition of the (-)-isomer by the (+)-isomer at CYP3A
The truth about the lower plasma concentration of the (-)-isomer after racemic doxazosin administration in rats: Stereoselective inhibition of the (-)-isomer by the (+)-isomer at CYP3A
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DOI：
10.1016/j.ejps.2015.06.022
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发表时间：
2015-09-18
影响因子：
4.6
通讯作者：
Ren, Leiming
中科院分区：
文献类型：
--
作者：
Kong, Dezhi;Li, Qing;Ren, Leiming
Doxazosin （DOX）是一种长效α(1)-肾上腺素能受体拮抗剂，临床使用的是由两种光学异构体组成的外消旋体。在人类和大鼠中，口服外消旋DOX [(+/-)-DOX]后，(-)-异构体的血浆浓度低于(+)-异构体，但这种相互作用的机制尚不清楚。本研究采用荧光检测手性高效液相色谱法测定药物浓度，在体内和体外实验中分析DOX的立体选择性代谢。我们发现(-)-同分异构体的血浆水平明显低于(+)-对映体，(-)- dox （0.0107 +/- 0.0007 L/min）的耗损速率常数（k(dep)）明显大于(+)- dox (k(dep) 0.0088 +/- 0.0005 L/min) (p
Doxazosin (DOX), a long-lasting alpha(1)-adrenoceptor antagonist, is used clinically as a racemate that consists of two optical isomers. In humans and rats, following oral administration of racemic DOX [(+/-)-DOX], the plasma concentration of the (-)-isomer is lower than that of the (+)-isomer, but the mechanism for this interaction is not known. In this study, a chiral HPLC with fluorescence detection was used to measure the drug concentrations for analysis of the stereoselective metabolism of DOX in in vivo and in vitro experiments. We found that the plasma levels of the (-)-isomer were significantly lower than those of the (+)-enantiomer following i.v. administration of (+/-)-DOX to the rats and that the depletion rate constant (k(dep)) of (-)-DOX (0.0107 +/- 0.0007 L/min) was significantly larger than that of (+)-DOX (k(dep) 0.0088 +/- 0.0005 L/min) (p