The Non-clinical Pharmacokinetics Of Crebanine

Crebanine, which mainly lies in some Stephania plants of Menispermaceae, is an isoquinoline aporphine alkaloids. Crebanine have many kinds of pharmacological actions and its antiarhythmia effect has been proved by animal experiments. The aim of this thesis is to study the non-clinical pharmacokinetics of Crebanine injection and to get a fundamental to make crebanine the first kind antiarrahythmia new drug of TCM. The contents of this thesis are as follows.First, the pharmacokinetics of Crebanine in rats . The plasma concentration of Crebanine in male and female rats at different times was determined by HPLC the data was analyzed with the DAS(ver1.0) software. The result showed Crebanine was deposed as one-compartment model in male and female rats. The t-test was applied to compare the pharmacokinetic parameters between male and female rats, the results revealed no obviously different. That is, there was no sexual different pharmacokinetic of Crebanine in rats. The mainly parameters : t1/2α=39.66±3.92min , Cmax=6.56±0.31mg·L-1,CL=0.055±0.005L·min-1·kg-1 ,Vd=2.95±0.28L·kg-1 , AUC = 384.13±33.05 mg·min·L-1 , A = 6.73±0.31mg·L-1 ,αKe=0.018±0.002 min-1Second, the tissue distribution of Crebanine in rats . The concentrations of Crebanine in 6 organs of rats were studied. Results showed that all of these organs contain Crebanine after injection. The order of the concentration according to high to low in these organs is lung, spleen, kidney, liver, brain and heart. The issue concentration obviously declined with the lapse of time.Third, the banding rates of Crebanine to plasma protein of rats . The banding of Crebanine to plasma proteins of rats was determined by equilibrium dialysis method. The result showed that the plasma protein binding rates of Crebnine were (91.71±0.90)%,(95.62±0.45)%,(96.21±0.54)% with the concentration 1×10-2,2.5×10-3,1.25×10-3mg/mL respectively. It indicated there was a high plasma protein binding rates of Crebnine in rats.Forth, the excretion of Crebanine in rats . The excretion rules of Crebanine in rats with metabolism cages were studied after injection, there were only 1.41 percent of Crebanine was excretion by urine in 24 hours. The concentration of Crebanine couldn't be determined in stool so there was no excretion of prototype Crebanine by stool.Fifty, the pharmacokinetics of Crebanine in rabbits . Blood serum was sampled from the rabbits'ears at different time which injected the Cre by 2.0mg·kg-1 and the concentration of Cre in blood serum was determined by HPLC. The pharmacokinetic parameters were accessed by the DAS software. The results showed Cre was fitted to a two compartment open pharmacokinetic model in rabbits. There was no different between the male and female rabbits'pharmacokinetic by t-test. The mainly pharmacokinetic parameters : t1/2α=3.25±0.22min ,t1/2β=36.67±5.52min, Cmax=1.40±0.06mg·L-1,CL=0.051±0.003L·min-1·kg-1 ,Vd=5.93±0.88 L·kg-1 ,AUC=39.56±2.43 mg·min·L-1,A =2.71±0.52mg·L-1,B=0.53±0.17 mg·L-1,α=0.22±0.02min-1,β=0.019±0.003 min-1。...