多组分中药血塞通注射液在脑缺血患者体内的群体药动学及药效学研究

摘要

AIM: Pharmacokinetic and pharmacodynamic profiles of Xuesaitong injection in cerebral ischemic patients are investigated in order to optimize dosage regimen of multiple constituent TCM in clinic. METHODS: 63 patients were studied in our protocol. Enumeration and measurement data of all patients were collected during our experiment. Blood samples were collected for two times at different time after intravenous infusion Xuesaitong injection at the dosage of 800 mg/kg for two weeks. Concentration of Xuesaitong injection in plasma, prothrombin time(PT), thrombin time(TT), activated partial thromboplastin time(APTT)and fibrinogen(Fib) were determined. NONMEM and SAAMⅡ were employed for the simulation of PPK parameters and time-course fitting of Xuesaitong injection in cerebral ischemic patients. RESULTS: Population pharmacokinetic (PPK) parameters of Xuesaitong injection obtained as follow: CL1: 1.5 L·h-1·kg-1, CL2: 13.0 L·h-1·kg-1, k10: 0.1136/h, k12: 0.9848/h, k21: 0.2057/h. Inter-individual variability were 36.3%, 17.8%, 1.0% and 60.3%. Residual variability was 8.67%. Age, stature, gender of patients showed no correlation with the prolong ratio of PT(PT%), TT(TT%), APTT(APTT%) and inhibit ratio of Fib(Fib%) whereas dosage (weight), infusion ratio and concentration of Xuesaitong injection in plasma were marked correlation to PT%, TT%, APTT% and Fib%. Correlation coefficient between dosage, infusion ratio, plasma concentration to PT%, TT%, APTT% and Fib% were 0.598, 0.551, 0.590, 0.505; 0.204, 0.401, 0.348, 0.403 and 0.560, 0.436, 0.593, 0.351, respectively. P value was less than 0.01 or 0.05. Best pharmacological effect obtained when Xuesaitong injection was administered as follow: Dosage was of 12.0-17.0 mg/kg, infusion ratio was of 10.0-18.0 mg/min and plasma concentration was of 25.0-35.0 μg/mL. Time course of Xuesaitong injection in cerebral ischemic patients was successfully predicted and simulated results suggested that better effects were obtained at the dosage of 800-1 200 mg/d than 200-400 mg/d. AUC 800-1 200 mg/d over the concentration range of 15-40 μg/mL in plasma was 32.99-77.33 mg·L-1·h when the infusion ratio of Xuesaitong injection was 10-14 mg/min whereas nothing or little at the dosage of 200-400 mg/d. CONCLUSION: Multiple constituent TCM population pharmacokinetic and pharmacodynamic profiles are successfully evaluated in cerebral ischemic patients. It gives us some information for the dosage regimen optimization in clinic for increasing therapeutic effect and reducing toxic reaction of multiple constituent TCM.