TY - JOUR AU - Feng Sheng AU - Jiang Ji AU - Hu Pei AU - Zhang Jian-yan AU - Liu Tao AU - Zhao Qian AU - Li Bi-lu PY - 2016 TI - A phase I study on pharmacokinetics and pharmacodynamics of higenamine in healthy Chinese subjects JF - Acta Pharmacologica Sinica; Vol 33, No 11 (November 2012): Acta Pharmacologica Sinica (Special Feature: Pharmacometrics) Y2 - 2016 KW - N2 - Aim: To investigate the pharmacokinetics, pharmacodynamics, and safety of higenamine, an active ingredient of Aconite root , in healthy Chinese volunteers. Methods: Ten subjects received continuous, intravenous infusion of higenamine at gradually escalating doses from 0.5 to 4.0 μg·kg −1 ·min −1 , each dose was given for 3 min. Blood and urine samples were collected at designated time points to measure the concentrations of higenamine. Pharmacodynamics was assessed by measuring the subject's heart rate. A nonlinear mixed-effect modeling approach, using the software Phoenix NLME, was used to model the plasma concentration-time profiles and heart rate. Results: Peak concentrations ( C max ) of higenamine ranged from 15.1 to 44.0 ng/mL. The half-life of higenamine was 0.133 h (range, 0.107–0.166 h), while the area under concentration-time curve (AUC), extrapolated to infinity, was 5.39 ng·h·mL −1 (range, 3.2-6.8 ng·h·mL −1 ). The volume of distribution (V) was 48 L (range, 30.8–80.6 L). The total clearance (CL) was 249 L/h (range, 199-336 L/h). Within 8 h, 9.3% (range, 4.6%–12.4%) of higenamine was recovered in the urine. The pharmacokinetics of higenamine was successfully described using a two-compartment model with nonlinear clearance. In the pharmacodynamic model, heart rates were related to the plasma drug concentrations using a simple direct effect model with baseline. The E 0 , E max , and EC 50 were 68 bpm, 73 bpm and 8.1 μg/L, respectively. Conclusion: Higenamine has desirable pharmacokinetic and pharmacodynamic characteristics. The results provide important information for future clinical studies on higenamine. UR - http://www.chinaphar.com/article/view/4305