Study On The Chiral Separaton And Its Pharmacokinetics And Pharmacodynamic Of Ranolazine Enantiomers

Ranolazine is a drug with a new mechanism for the treatment of angina pectoris, It is a novel drug for the treatment of stable angina pectoris and was developed by the company of CV Therapeutics and Kissei. And the U.S. Food and Drug Administration approved ranolazine listing in2006. Ranolazine is a piperazine compounds, There are a pair of optical isomers and a chiral center in its molecules. But up to today, ranolazine is still in the stage of research and development in China and not listed. According to the relevant regulations of the National chiral drugs listed: Chiral drugs must be investigated in its pharmacodynamic, and toxicology if declared.This study established a method of chiral separation of optical isomers RNZ, using chiral column CHIRALPAK IC, and also study RNZ and its optical isomers pharmacokinetics in rats. We studyed whether RNZ and its optical isomers playing a protective role on myocardial ischemia-reperfusion injury by establishing an Isolated rat heart model of ischemia-reperfusion. And then, taking an observation of RNZ and its optical isomers, whether they are both play a protective role on myocardial ischemia-reperfusion injury. It can provide a reference value on the developing of R-RNZ and S-RNZ, pharmacokinetic parameters and rational drug use.Part One The chiral separation of Ranolazine.Purpose:Establishing a method to separate RNZ optical isomers, and identificatng the structure of the resulting monomer. Layying a foundation for its pharmaco-kinetic and pharmacodynamic study. Method:Chiral column:CHIRLPAK IC0.46cm I.D×25cm L; Column temperature:35℃, Mobilephase:Ethanol/Triethylamine=100:0.1(v/v);Detection wavelength:uv220nm; Velocity of flow:0.4ml/min.Results:Establishing the method of chiralling split the RNZ optical isomers and succeed in getting the monomers we needs. Identifing the peak of1is R-RNZ,and the peak of2is S-RNZ.Conclusion:the method we established has a high specificity, high sensitivity, under this method we succeeded in chiral separation of ranolazine.and the baseline is completed separation. The analysis methods established in this experiment meets the requirements of analysising the chiral separation of actual sample and also meets the requirements of chromatography prepared split.Part two The pharmacokinetic study of Ranolazine and its optical isomers Purpose:AIM To study the pharmacokinetics of Ranolazine and its optical isomers in rat plasma. METHODS The chromatographic separation was achieved on a YMC-Pack ODS-A(150x4.6mm,5μm) and Phenacetin as internal standard, The mobile phase consisted of acetonitrile-buffer (0.05mol/L K2HPO4solution containing1‰triethylamine,pH=6.5)=40:60,v/v), at a flow rate of1mL·min-1;Twenty-seven SD rats were randomly divided into nine groups, The nine groups received Ranolazine and its optical isomers at single dose of12.5mg/kg,25mg/kg,50mg/kg, respectively.The concentrations of Ranolazine in rats plasma at different time were determined by HPLC and the pharmacokinetic parameters were calculated. CONCLUSION Statistical results show that the value of Cmax,Tmax, t1/2and AUC of R-Ranolazine and S-Ranolazine had no significant difference (p＞0.05),Ranolazine compared with different optical isomer has good absorption in the body.Part three:Myocardial preservation effects of RNZ and its optical isomers on myocardial ischemia/Reperfusion injury in isolated rat heartsObjective To understand its optical isomers and racemic myocardial protective effect of reperfusion, through the establishment of ischemia-reperfusion model, observation of RNZ, R-RNZ, and the S-RNZ isolated myocardial ischemia in ratsinjury. Methods:30SD rats were randomly divided into five groups that continue to be absorbed in the group, ischemia-reperfusion group (I/R group) the the RNZ racemic group (RNZ group),RNZ dextral group (R-ranolazine group), RNZ the sinistral group of (S-the ranolazine group), n=6, to establish the isolated rat hearts Langedorff model, record hemodynamic changes, collect the balance at the end of the end of reperfusion coronary effluent measured in the liquid content of creatine kinase, lactate dehydrogenase, as well as the activity of ATP. Results:RNZ its optical isomers on myocardial ischemia reperfusion-induced myocardial injury is more significant role of the protective effect of ranolazine group, R-ranolazine followed.