| YM0302, a first-line drug for treating benign prostatic hyperplasia(BPH), is a piperazineα1-AR antagonist. It works by selectively acting onα1A-AR andα1D-AR located in bladder neck, prostatic capsule and hyperplastic stroma of prostatic. Meanwhile, YM0302 exhibited low cardiovascular effects simultaneously because of low activity forα1B-AR. In terms of structure, YM0302 possesses a chiral center , so that there are two enantiomers. The preliminary study of our team indicated that pharmacologic variability existed between YM0302 enantiomers, which encouraged us to understand enantioselective pharmacokinetics of them in order to apply this drug properly. Additionally, the further study of stereoselective metabolism provides references for design of new drugs by structural modification accroding to improvement of some internal process.The work developed in this dissertation is as follows:1. Accroding to the"Instructive principle for preclinic study of new drug"of China Pharmacopoeia 2005 edition Part Two and"Guidelines of Chiral drug quality control technical", conduct research on quality of two enantiomers of YM0302 respectively, and formulate the quality standard draft of YM0302 enantiomers.2. Established a HPLC method for bioanalysis of YM0302 enantiomers, which employed Chiralpak IA as chiral solid phase and mixture (methanol : acetonitrile : 50mM ammonium formate aqueous solution ( adjusted pH to 5.3 by fomic acid ) : DEA v/v/v/v = 35:35:30:0.1 ) as mobile phase. Flow rate was 0.5ml/min; column temperature was 25℃; Fluorescence detector was used with 290nm as excitation wavelength and 340nm as emission wavelength. Avoiding interference of endogenic impurities and metabolites, R-YM0302 and S-YM0302 was excellently separated, which indicated this bioanalysis was time-saving and easy. Over the concentration range of 6.25~1000ng/mL, the linearities( r>0.99 ), recoveries (85%～115%) and precision (<10%) are all satisfied for the determination.3. The pharmacokinetics of R-YM0302 and S-YM0302 were developed to explore the kinetic variation so as to study the biological behavior differences between the YM0302 enantiomers. After intravenous administration with 5mg/kg YM0302 enantiomers, the results showed that the pharmacokinetics of YM0302 enantiomers in rat plasma complied with two-compartment model. After intragastric adiministration with three levels dosage, analyse drug-time curve with non-compartment modle, the results showed that pharmacokinetics parameters of YM0302 enantiomers were partially different. At low dosage, the ratio of Cmax was 1.466 (S/R), which performed as 1.372 at middle level. At high level dosage Tmax of R-YM0302 and S-YM0302 were 1h and 0.55h respectively. Compariting AUC of two enantiomers with intravenous and extravenous route, absolute bioavailability of R-YM0302 and S-YM0302 were calculated to be 22.0%±10.5% and 41.4%±11.0% respctively.4. The distribution study of YM0302 enantiomers in rats employed I125-labelled compound. It stated clearly that the highest radioactive concentration appeared in small intestine and liver, which were primary organs to absorb and digest YM0302 enantiomers. Bladder and prostate were detected with high radioactive concentration followed small intestine and liver, which were exactly targets of YM0302 raceme, and radioactive concentration there raised as time went on.5. After a single intragastric adiministration of R-YM0302 and S-YM0302 20mg/kg, the urine and feces of rats were collected and researched. The result showed that the accumulative urine and feces contained few unchanged YM0302 enantiomers, but enantiomers existed enantioselective in this two excretion routes-S-YM0302 in urine was more than R-YM0302, the opposite result appeared in feces. Combining with plasma concentration of YM0302 enantiomers, we inferred that there were enantioselective actions existed in first-pass effect and glomerular filtration. Besides, majority of R-YM0302 and S-YM0302 turned to be metabolites and eliminated through feces, because more unknown metabolites came up in feces than that in urine and plasma.
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