Neuropharmacokinetic Study Of L-DOPA In Rats Based On The Microdialysis Technology And Establishment Of Rat Model Of Parkinson's Disease

Objective1. To evaluate the pharmacokinetics(PK) of levodopa(LD) in striatal extracelluar fluid and in plasma of rats after an intragastrical administration of Madopar (LD with benserazide) and analyse the relativity of them;2. To establish a steady rat model of Parkinson's disease.Methods1. Experiments were performed on 250-280g male Sprague-Dawley rats. 14 rats were divided by two groups: LD/BZE(48/12mg?kg-1)administration group,n=7 and LD/BZE(48/12 mg?kg-1) administration group,n=7. Dialysate of striatum were collected by microdialysis and blood samples were drawn from rats simultaneously. The concentrations of LD in striatal extracelluar fluid and plasma were determined by HPLC-ECD.Evaluate the PK parameter of LD in striatal extracelluar fluid and in plasma of rats with the application of NONlinear Mixed Effects Model(NONMEM) and the pharmacokinetic software of 3p97;2. Build up Parkinson's disease model rat by direct injection 6-Hydroxy Dopamine (6-OHDA,12μg·4μL-1) into the medial forebrain bundle (MFB) and substantia nigra pars compacta(SNc) with stereotactic technique. Apomorphine (1mg·kg-1) was intraperitoneal injected to evocate circle behavior. Choose the rats rotated over 7 turns per min which are the accurate models.Results1. I t is found that the pharmacokinetic of LD in striatal extracelluar fluid differs from plasma. Compared with the plasma, time to reach Cmax(tmax ) is much longer in striatal extracelluar fluid and maximum concentration(Cmax ) and area under the concentration-time curve(AUC0→∞) of LD is much smaller, while the ratio of the two AUC0→∞is constant(about 3%) .There is some relativity between the concentration of LD in striatal extracelluar fluid and plasma. With the analyse of NONMEM, it is found that weight can affect none of the LD pharmacokinetic parameters except for K32, while dosage have no effect to any PK paremeter.2. A few rat models of Parkinson's disease which accounts for 27.5 percents of the total is established.Conclusion1. The combination of microdialysis technology and HPLC-ECD is applicable to the neuropharmacokinetic study of LD.2. With the application of NONMEM,a statistic model of LD that include the effect of weight,dosage,variability between individuals and intraindividual variation is established,which is capable of depicting the pharmacokinetic of LD in striatal extracelluar fluid and plasma.3. A steady and successful rat model of Parkinson's disease is established by unilateral lesioned of 6-OHDA.