| ObjectiveTo establish the determination method of TMC in the blood plasma and the tissue, use this method to analysis the concentration-time procedure and tissue distribution of TMC in rats, then we do the study of pharmacokinetics of TMC in Rats.MethodsWiatar rats are injected TMC in tail vein for40mg/kg,80mg/kg,160mg/kg dose, then collect the blood0.5ml respectively befor and after administration1,3,5,10,15,20,30,45min,1,1.5,2h, after be precipitated protein by acetonitrile, it can be derivatized with2,4-dinitrofluorobenzen (DNFB) for the determination, by HPLC (reversed-phase Venusil C18colomn A:0.05mol/L CH3COONa (pH6.0); B: CH3CN-H2O (50:50, v/v) as mobile phase, detection at360nm), so the TMC content in the plasma can be determined, according the determine results to draw the concentration-time curve and calculate the pharmacokinetics parameters.Wiatar rats are injected TMC in tail vein for80mg/kg dose, execute the rats befor and after administration10,30min,1,2,4,8h respectively, collect the tissue (heart, liver, brain, kindey), add Sodium Chloride in it according to the1g:10ml ratio, Prepares the organization homogenate use the homogenate machine. After be precipitated protein by acetonitrile, it can be derivatized with2,4-dinitrofluorobenzen (DNFB) for the determination, the content of tissue can be determined by the same reversed-phase HPLC method like plasma determination.ResultsTMC can determined in the plasma quichly after iv in dose of40mg/kg,80mg/kg,160mg/kg, the concentration-time profile of TMC in rats were shown to fit one-compartment nonlinear pharmacokinetic model, the pharmacokinetics parameters T1/2were20.61±3.53,37.36±7.30and77.55±5.44min respectively, Co were317.28±11.84,477.63±48.35and818.02±43.11μg/ml respectively, CLs were0.004±0.001,0.004±0.0005and0.002±0.0002μg/ml/min respectively, AUC(0-t) were10132.0±247.5,18305.5±1664.4and59508.6±3759.4μg/ml/min respectively;There is significant difference among the three dosage groups about T1/2(P<0.01), the AUC(0-t) were decreased along with the dosage, but not along the proportion; MRT(0-t) wree28.579±1.05,42.549±1.24and49.701±0.86min respectively. TMC can determined in the main tissue(heart, liver, brain, kindey)quichly after iv in dose of80mg/kg, At10min after iv administration, the top tissue content was found in heart, the second tissue content was foud in liver and kindy, and the lowest content was detected in brain. Till to1h, the content in heart were decreased and in liver and kindey were not change a lot, the lowest concent was still in brain. In2h the content in liver was not change obviously, the speed of elimination was slow, after2h the speed became quicker, the change procedure in kindey was similar as liver. After iv administration8h, the content in heart was the lowest and in kindey was the hignest. The content in brain was low and not change a lot along with the time.Conclusion1. This study eatablished the HPLC method to determine the TMC content in rat plasma and main tissue (heart, liver, brain, kindey), it can work on the study of pharmacokinetics in rats.2. Rats were administrated in tail vein by single dose of40mg/kg,80mg/kg,160mg/kg, the pharmacokinetics behavior was found to fit one-compartment nonlinear pharmacokinetic model.3. Rats were administrated in tail vein by single dose of80mg/kg, the highest cocentration was found in heart and the lowest in brain. |
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