Enantiomer Seperation Of Terazosin In Vitro And The Study On It’s Stereoslectivity In Pharmacokinetics

The quinazoline-derivative, terazosin, is a selective postsynaptic α1_adrenergic blocking agent for the treatment of essential hypertension and benign prostatic hyperplasia in clinical pratice. In this paper, a HPLC method was established for the determination of terazosin enantiomer. The method was applied to the content determination of terazosin’s enantiomers in Terazosin Hydrochloride tablets and for their stereoselective pharmacokinetics study in human, which laid a foundation for further exploitation terazosin’s preparation development and rational clinical administration.1. A HPLC-UV method was established for terazosin’s enantiomeric separation. Baseline chiral separation was performed under normal-phase mode by the Chiralpak AD-H chiral column to study the influences of the composition of the mobile phase, the flow rate, and column temperature for the terazosin’s enantiomeric separation. The optimal chromatographic conditions adopted hexane-isopropyl alcohol-diethylamine (65:35:0.1) as the mobile phase at the flow rate of0.7mL/min and chose detection wavelength of254nm while the column temperature was set to25℃. Under the above chromatographic conditions, the resolution between the peaks of terazosin’s enantiomers was3.1. The two enantiomers were found to be linear correlation in the2.50～7.50μg/mL range, with99.8%and99.4%average recoveries, respectively. Therefore, this approach could be successfully applied for the content determination of terazosin samples.2. A selective and sensitive liquid chromatography with fluorescence detection was also developed for the determination of terazosin in human plasma. The analyte and internal standard (I.S.), doxazosin, were extracted from plasma via liquid-liquid extraction with diethylether:dichlormethane (3:2) and separated on a Chiralpak AD-H column (4.6mm×250mm,5.0μm) using hexane-alcohol-diethylamine (52:48:0.1) as mobile phase at a flow rate of0.8mL/min. Detection was through fluorescence detector at the excitation wavelength of270nm and emission wavelength of375nm. The assay was linear dependence over the concentration range of0.500～75.0ng/mL for the analyte. The lower limit of quantification (LLOQ) was0.500ng/mL in human plasma with intra-and inter-day precision (R.S.D.)<15%and accuracy as relative error (R.E.) within±15%. 3. The method was successfully applied to the determination of terazosin’s enantiomers in human plasma, and their stereoselectivity in pharmacokinetic study. This research was conducted in12volunteers after a single, oral dose of Terazosin Hydrochloride tablets under fasting conditions. The drug concentrations in volunteers’ plasma were detected and then the corresponding pharmacokinetic parameters were calculated. The statistic result is shown as follows:compared to (S)-terazosin,(R)-terazosin exhibited higher absorption degree and system exposure with lower elimination rate, indicating the stereo-selectivity of terazosin’s metabolism in human. Considering the fact that (R)-terazosin has less side effects than (S)-terazosin, if terazosin could be administrated as a pure enantiomer, it may demonstrate better pharmacological effect than the racemic formulation.