Pharmacokinetics Of Sinomenine

Background and purpose:Sinomenine is extracted from traditional Chinese crude drug--Caulis Sinomenii, which is used for therapy of beriberoid disease and Rheumatoid disease,and applicated widespeadly in clinic,main effects of it are anti-inflammatory,immune suppression,analgesia,depressurization,anti-arhythmia,resisting addiction of morphine.as a sort of important Chinese traditional crude drug, It is more than1000 years when Caulis Sinomenii was used in clinic.Recently,because of its conspicuous effects on dealing HBP,CA,CVD,drug addiction, pharmacology studying about Sinomenine is more and more extensively. Long-term administration is needed when sinomenine treat rheumatic disease,pain,arthrophlogosis,chronic nephritis,addiction of morphin.Literatural about pharmacokinetics of Sinomenine is very few,it is short of detail and available datas .Administration style of Sinomenine from literature is injection mostly[17][18],but in fact,oral administration is the most adopted style in clinic.There is no literature reported the bioequiavailability of sinomenine .Dispute existed about the concentration detection methods of Sinomenine,some paper indicates that the methods of concentration detection according to pharmacopeia is needed modified[8]. On trial of treat abstinent symptom of addiction of morphine ,the effect of sinomenine is excellent and the side-effcts is little,what is more,it is no addiction from itself .Some paper pointed out that sinomenine can permeation BBB,but there is no papers about distribution of Sinomenine in mice brain.so,this paper has reported pharmacokinetics of Sinomenine in rabbits,bioequiavailability of two kind of sinomenine praeparatum on market,steady state pharmacokinetics of Sinomenine in rabbits and distribution of sinomenine in encephalic region of mice.Method (1)Pharmacokinetics of Sinomenine in rabbits:each of six rabbits are intragastricly administrated Sinomenine with dosage of 45mg·kg^-1,blood sample is obtained when 0.25,0.5,1.0,1.5,2.0,3.0,4.0,6.0,8.0,10.0,12.0h after administration,then set up HPLC method for detection blood drug concentration of Sinomenine in rabbit and to invest the pharmacokinetics; ( 2 ) Steady state pharmacokinetics of Sinomenine in rabbits: rabbits are administrated with Sinomenine 4 times a day,with the dosage of 15mg·kg^-1,the blood samples are obtained when 0.25,0.5,1.0,1.5,2.0,4.0,6.0,8.0,12.0h after reaching steady state.blood concentrations are determined by HPLC and datas are dealed with 3P97 software,then explore the character of steady state pharmacokinetics in rabbits of Sinomenine;(3)bioequiavailability of two kind of sinomenine praeparatum(HN and XA): A single dose of 45mg·kg^-1 Sinomenine preparation was administrated by randomized crossover way in rabbits. the blood samples are obtained when 0.25,0.5,1.0,1.5,2.0,4.0,8 .0, 12.0 h after reaching steady state.Blood concentrations are determined by HPLC .Then explore the pharmacokinetics and bioequivalence of two kinds of sinomenine praeparatum(4)Distribution of Sinomenine in mice brain tissue:90 mice are divided into 3 groups randomly,each group has 30 mice,mouse in big dosage group,middle dosage group,little dosage group are intragastricly administrated Sinomenine with dosage of 116 mg·kg^-1,58 mg·kg^-1,29 mg·kg^-1 randomly , cerebrum,deutocerebrum and cerebellar of mice tissue are obtained when 3 hours after administration.Then explore the distribution of Sinemenine in cerebrum,deutocerebrum and cerebellar of mice.Result:(1)Pharmacokinetics of Sinomenine after single dosage administration in rabbits: T1/2(Ka) was(0.31±0.26)h,T1/2(Ke) was(3.15±0.82) h,T max wa(s1.05±0.53)h,Cmax wa(s15.09±4.15)μg·mL^-1, AUC0→T was(78.29±13.46)μg·h·L^-1,AUC0→∞was(84.27±13.02)μg·h·L^-1,(2)Steady state pharmacokinetic parameters of sinomenine in rabbite: Cssmax was 7.32μg·mL^-1,Cssmin was 4.58μg·mL^-1 , C ss was 5.05μg·mL^-1,AUC0→T was (30.31±13.46)μg·h·L^-1,AUC0→∞was 31.27±11.34μg·h·L^-1 ,DF was 80.83%±13.68%。(3)bioequiavailability of two kind of Sinomenine preparation:drug-time curve of two kind of Sinomenine preparation present single compartment model, Tmax are(0.81±0.34)h and(0. 60±0.30)h respectively, Cmax was (11.16±0.58)μg·mL^-1 and ( 11.90±1.44 )μg·mL^-1 respectively , AUC0→T was (61.58±6.70)μg·h·L^-1 and (60.56±6.67)μg·h·L^-1respectively, Suggesting no significant diffirence between the main pharmacokinetic parameters of two prepations(P﹥0.05),relative bioavailability was 102.77%±15.63%; (4)Distribution of Sinomenine in mice brain tissue:In cerebrum,deutocerebrum and cerebellar of mice,the distribution concentration of big-dosage sinomenine group are 1.33μg·g(brain tissue)^-1,2.06μg·g(brain tissue)^-1,4.53μg·g(brain tissue)^-1 respectively,middle-dosage Sinomenine group are 1.09μg·g(brain tissue)^-1,3.40μg·g(brain tissue)^-1,2.50μg·g(brain tissue)^-1 respectively,little- dosage Sinomenine group are 0.82μg·g(brain tissue)^-1,2.62μg·g(brain tissue)^-1,2.23μg·g(brain tissue)^-1 respectively。Conclusion:The HPLC method of our experiment is sensitiveness, fast and stable ; after intragastric administration, Sinomenine was distributed as single compartment model, metabolism of Sinomenine is very soon and T1/2 is short;it is reach steady state after 5 administrations or so according to our determination ; two kind of Sinomenine are bioequivalent;The concentration of Sinomenine in deutocerebrum of mice is higher than that in cerebrum or cerebellar of mice obviousely.