Pharmacokinetic Studies And Tissue Distribution Of YHX-11

Diabetes has gradually become the global problem today. It not onlyseriously affect the patient’s quality of life but also bring huge burden onsociety. Vildagliptin is an effective diabetes drug of type Ⅱand it had beenapproved by the European Union in2008. It not only can been used alonebut also can been combinated to traditional oral glucose-loweringmedications ineffective to treat for diabetes of typeⅡ. Vildagliptin is a kindof DPP-Ⅳ inhibitors of competitive, selectivity and reversibility. Clinicalpractice had proved its hypoglycemic effect obvious. It doesn’t causehypoglycemia and weight gainand. Other adverse reactions are also small.Itapply widely.The structure modification of Vildagliptin is a hotspot of currentresearch and it has certain practical value. According to the successfulexperience of lipoci vildagliptin made by professor Xu Wenfang ofshandong university, geting a series of type structure on the secondarynitrogen of the Vildagliptin is possible. The derivatives were tested in vitroactivity screening of derivatives. The derivatives were mainly detected IC50of DPP-4. A Vildagliptin was made as reference. These derivatives were confirmed whether really had the value of the drug development. Ourexperiments were to confirm the activity screening of derivatives gettingfrom the medicine laboratory of college. Pharmacokinetic and tissuedistribution were studied to investigate pharmacological properties of thederivatives. These pharmacological data should be useful for new drugresearch as a candidate.The first part:Objective: To establish a high performance liquid chromatography(HPLC) method for the determination of YHX-11in plasma of rat andverify it. Methods：The Agilent C-18(250mm x4.5mm,5um) was usedas chromatographic separation and Agilent C18pre-column (40mm x3.0mm,5um) was used as protecting column with mobile phase of10mmol/LKH2PO4–Methanol (35:65).The column temperature was25℃and the flowrate was1.0mL/min.The detection of wavelength was276nm.Results:Adopting the HPLC method for determining YHX-11in rat plasma,thepeaks in biological samples were good.The standard curve was lineared inthe range of37.5ng/mL～6000.0ng/mL and the related coefficient was0.9998. The limit detection of YHX-11in plasma was37.5ng/mL.Theextraction recovery was90.51%～93.64%and the RSD were7.78%,6.37%and7.14%for the low concentration, medium concentration and highconcentration. The method recovery was97.96%～102.27%and the RSDwere6.29%,5.30%and5.98%for the low concentration, medium concentration and high concentration.The within-day RSD and between-dayRSD were less than11.04%and13.07%respectively. Conclusions: Themethod used for determineation of YHX-11in rats plasma is of highsensitivity, precision and repeatability. It can determine the content ofYHX-11in rat plasma accurately. It can be used to the pharmacokineticstudies of YHX-11in rat plasma.The second part:Objective: Make animal research and test the biological samples to studythe tissue distribution in rats by HPLC. Methods：18rats were the studyobject which were grouped randomly.There were divided into six groupswith test of distribution phase, balance phase and elimination phase.Eachgroup of the animals were administered by oral respectively for YHX-11of30mg/kg. The rats were executed at the time point of15,30,90min andorganizations in the same location were cuted appropriately to determine thecontent. Results: Adopting the HPLC method for determining YHX-11inrat tissues,the peaks in biological samples were good.The standard curveswere lineared in the range of37.5ng/mL～6000.0ng/mL(r≥0.9995). Theextraction recovery was84.72%～95.64%and the analytical recovery was97.53%～103.43%.The within-day RSD and between-day RSD were lessthan11.69%and14.85%respectively. The limit detection of YHX-11intissues was37.5ng/mL. YHX-11distributed widely in tissues.Conclusions:The method used for determineation of YHX-11in rats tissues is of high accurately. After giving YHX-11, the drug distributed rapidly andpenetrated strong. It distributed widely in the body. The concentration ofdrug was high in lung,liver,kidney,heart and brain.