Pharmacokinetic And Tissue Distribution Studies Of Vildagliptin Derivative YHX-13

There is an upward trend of the prevalence of diabetes nowadays. It hasbecome the third largest killer of human life and health after tumor andcardiovascular disease. China has become the fastest growing areas of globaldiabetes and the biggest of the world. Patients of China is given priority withtype II diabetes, the proportion has reached93.7%. DDP-IV inhibitors as anew type of oral hypoglycemic drugs for blood glucose control in type2diabetes, efficiency treatment, good safety and tolerability had beenconfirmed in a large number of clinical trials and practical application.Vildagliptin is a highly selective DDP-IV substrate inhibitor, combinedwith DDP-IV by reversible covalent bond, disintegrate slowly, thedissociation time could reach55min, thus it can be more potent inhibitionto DDP-IV activity. The chemical laboratory of Chongqing medicaluniversity get a series of Vildagliptin derivatives by means of Vildagliptinstructure modification, and living screening in vitro, YHX-13is one of thegood active derivatives. This experiment by pharmacokinetic and tissuedistribution study of YHX-13, can examine the pharmacological propertiesof the derivatives, to provide theoretical basis for the research anddevelopment of new drugs. The first chapter: Established the detection method andpharmacokinetic studies of Vildagliptin derivative YHX-13Objective: To establish a method for the determination of Vildagliptinderivatives YHX-13in plasma of rat, studied the regularity ofpharmacokinetic and bioavailability in mice. Methods: Dosed kunmingmice in two ways of lavage and tail intravenous, pointed orbital blood in thecorresponding time, used MCX solid-phase extraction to handle biologicalsamples, detected the concentration of YHX-13in plasma by highperformance liquid chromatography (HPLC) method, with acetonitrile andpotassium dihydrogen phosphate (40:60) as mobile phase, obtained relevantpharmacokinetic parameters and bioavailability. Results: The concentrationof Vildagliptin derivatives YHX-13in mice plasma were determined byHPLC method, the peak shape were good, and it could completely separatewith the internal standard, the linear relationship were good in the range of100ng/mL~4000ng/mL and the related coefficient was0.9993. Thewith-in day RSD were7.2%~12.2%, the between-days RSD were8.6%~13.3%. The recovery was96.7~106.65%and the RSD were4.86~6.01%.The stability at room temperature for24h and repeated freeze-thaw5timeswere good. The pharmacokinetic parameters of oral medicine generationwere Cmax=1557.11ng/mL, Tmax=30min, AUC0~∞=358232ng·min/mL,AUC0~t=159898ng·min/mL, CL=41.8723mL/min/kg, t1/2=740.784min,MRT=932.258min, Vss=39035.7mL/kg; The pharmacokinetic parameters of tail intravenous were Cmax=1610.22ng/mL, Tmax=3min,AUC0~∞=79203.6ng·min/mL, AUC0~t=66177.7ng·min/mL, CL=63.1284mL/min/kg, t1/2=101.103min, MRT=125.331min, Vss=7911.93mL/kg,bioavailability was80.54%. Conclusion: The related conditions of HPLCmethod for YHX-13in mice plasma levels have good detection sensitivity,high accuracy, and good repeatability, used in the study of YHX-13pharmacokinetic in mice, and can get good related parameters andbioavailability.The second chapter: Tissue distribution studies of Vildagliptinderivative YHX-13Objective: To establish a HPLC method for the determination ofYHX-13in the tissue of mice, and investigated its distribution in the tissue ofmice. Methods: Dosed Kunming mice by lavage, beheaded kill at the phasepoint of absorption, the phase point of distribution and the phase point ofelimination. Took out the heart, liver, spleen, lung, kidney, brain of thecorresponding time point, measure the concentration of YHX-13in eachgroup. Results: The peak of YHX-13in every tissue of mice serum couldseparate completely with internal standard peak, and did’t beeninterferenced from endogenous impurities in biological samples. The linearrelationship were good in the range of100ng/mL~4000ng/mL and therelated coefficient were greater than0.99; The with-in day RSD were lessthan11.01%, the between-days RSD were less than12.13%; The recovery was95.54%~95.54%and RSD were3.2%~8.66%, both could satisfy thetesting requirements of YHX-13in the biological sample. The stability atroom temperature for24h and repeated freeze-thaw5times were good.Conclusion: The HPLC method can detect the concentration of YHX-13inthe tissue of the mice accurately after lavage, YHX-13mainly distributed inthe lungs, followed by kidney, liver and spleen in a less distribution.