Quntification Of Racecadotril's Metabolite (Tiorphan) In Human Plasma And Their Appliction In Pharmacokinetics

Objective: To develope a mothod of measuring the racecadotril's metabolite Tiorphan by HPLC-MS/MS and to evaluate the pharmacokinetic characteristics of racecadotril dispersible tablet and dried suspension.Method and Results: 1. Acyclovir was taken as internal standard. The sample was precipitated with double amouts of acetonitrile and centrifugated for injection. The mobile phase was consist of acetonitrile and 0.05%acetic acid(70:30). A method of determining the concentration of Tiorphan in human plasma was established with an Ultimate XB-CN column. The calibration curves were linear over the concentration range of 1.984⁶56.0μg?L^-1, the lower limimt of quantification was 1.984μg?L^-1. The RSD values of intra-day and inter-day precision for the QC sample (3.928 ng·mL^-1,98.6 ng·mL^-1,459.2 ng·mL^-1) were below 15%, and the reproducibility and accuracy was good. The extraction recovery was 82.81⁹0.62% and the samples were stable in different conditions and had hardly matrix effect. After 22 Chinese volunteers were administrated an oral doze of 90mg racecadotril dispersible tablet, we got the main pharmacokinetic parameters: the value of T1/2 was (7.619±3.118)h,Cmax was found to be (223.834±100.062) ng·mL^-1,Tmax was (1.876±0.727)h,AUC(0→t) was (770.503±317.075) ng·h·mL^-1,AUC(0→∞) was (837.159±340.964) ng·h·mL^-1。2. The method of determining the concentration of Tiorphan in human plasma was founded by taking lisinopril as the interal standard. The linear range of the standard curve for Tiorphan was 3.938¹640 ng·mL^-1 . The RSDs of intra-day and inter-day were both lower than 15%, the extraction recovery and the stablity of Tiorphan in different conditions were determinated at three concentrations(9.84 ng·mL^-1,98.4 ng·mL^-1,1312.0 ng·mL^-1). The main pharmacokinetic parameters were obtained after administrating an oral doze of 90mg racecadotril dried suspension: the value of T1/2 was (7.42±2.69)h,Cmax was (703.94±315.39) ng·mL^-1, Tmax was (0.32±0.10)h, AUC(0→t) was(1052.93±398.60) ng·mL^-1·h and AUC(0→∞) was(1122.82±411.70) ng·mL^-1·h。Conclusion: The methods were proved to be sensitive , specific, speed and easy for clinical investigation of the formations of racecadotril.