Study Of Pharmacodynamics And Pharmacokinetics Of Methocarbamol Sodium Phosphate

Objective:To investigate the anticonvulsant and muscle relaxant effects of methocarbamol sodium phosphate?methocarbamol sodium phoshate,Me-Na?on mice.Establish a high performance liquid chromatography method in order to quantitative text methocarbamol,and then study the absorption,distribution,metabolism and excretion process after intragastric?i.g?and inject methocarbamol sodium phosphate?Me-Na?in rats,to investigate the pharmacokinetic characteristics of the drug in rats;Establish a high performance liquid chromatography metod in order to quantitative text methocarbamol in the tissue of mice,through the determination of methocarbamol concentration in tissue samples to study the distribution of Me-Na in mice brain,liver,kidney and muscle tissue after i.g or inject for single dose.Method:1.The mice were administrated a series of dose of Me-Na solution?231?462?924?1848mg/kg?though i.g and inject,the incidence rate and emergence time of convulsion in mice were recorded in order to observe the anti-convulsion effects of Me-Na;the grasping force and the rotating rod time of mice were detected in order to observe the muscle relaxation effects.And then the treatment effects of Me-Na were compared with Me?methocarbamol,Me?.2.Establish a high performance liquid chromatography method in order to quantitative text Me in rat blood,and then analyze the methodology.The rat were administrated a series of dose of Me-Na solution?128?256?512mg/kg?though i.g and inject,and object the vein blood for angulus oculi medialis at different time points.After treatment of plasma samples,determine the blood concentrion of Me by the method of HPLC established in this paper and calculate the pharmacokinetic parameters.3.Establish a high performance liquid chromatography method in order to quantitative text Me in mice tissues,and then analyze the methodology.The mice were given 924 mg/kg Me-Na equivalent to one time clinical dose by i.g and inject.The mice were killed at different time point,and then object the brain,liver,kidney and muscle immediately.After treatment of tissues samples,determine the blood concentrion of Me by the method of HPLC established in this paper.Draw the concentration-time curve of Me in different tissues of mice.Evaluation the distribution of Me-Na in mice.Results:1.On the study of pharmacodynamics of Me-Na,compare with the NS group,the different dose Me-Na can reduce the rate of convulsion and delay the time of convulsion;reduce the ratio of grasp and weight,the time of rotating was shortened significantly.2.On the study of Pharmacokinetics of Me-Na,?1?the concentration of Me from1.0 to 512?g/ml in blood samples is good linear relationgship?minimum weighted two multiplication?,r=0.9997;The minimum detection limit is 1?g/ml;the intra-and inter batch precision of low,medium and high concentrations RSD<10%,absolute recovery>90%,The recovery rate was 101.6%;The stability text of low,medium and high concentrations in the stability of the sample after 2 weeks of frozen thawed changes in the concentration of less than 15%.?2?given Me-Na for 128 mg/kg,256mg/kg,512 mg/kg by i.g for singnal,main pharmacokinetic parameters t_1/2 were0.86±0.28,1.50±0.47,2.74±1.31 h;C_max were 39.09±11.60,58.97±20.22,82.62±21.44?g/ml;AUC_?0-t?were 75.00±28.58,175.94±94.77?350.05±122.99??g/ml?*h.?3?given Me-Na for 128 mg/kg,256 mg/kg,512 mg/kg by inject for singnal,main pharmacokinetic parameters t_1/2 were 1.15±0.45,1.44±0.59,1.95±0.82h;C_maxwere 75.98±18.83,117.00±16.51,157.85±13.26?g/ml;AUC_?0-t?were145.36±53.64,270.57±109.38?467.52±210.05??g/ml?*h.3.The concentration of Me standard solution as abscissa,The measured peak area is ordinate,draw the standard curve corresponding to each organization and linear regression?weighted least square method?,in the concentration of 1²56?g/mL,there was a good linear relationship between peak area and concentration of Me,The lower limit is 1?g/mL.Accuracy and precision are between 90-110%,the RSD were less than 5%for the intra-and inter batch.The recovery and absolute recovery were in the range of 90-110%.Measured the concentration of Me in different tissues of mice by the method was established in this study.The results showed that in both brain and liver,kidney and muscle tissues were detected Me and showing the corresponding changes by i.g and inject for singnal.Conclusion:1.Me-Na has anti-convulsion and muscle relaxation effects on mice,and have the same clinical application effect compared with Me.2.The Me-Na which is given to rats by i.g almost all change as Me,the Me-Na which is given to rats by inject almost 95%change as Me.So we can study the pharmacokinetic characteristics of Me-Na by determine the Me.3.It can be seen from concentration-time curve,the process of pharmacokinetics in rats accord with the characteristics of one absorption one compartment open model after i.g or inject Me-Na.With the increase of the dose,the elimination half life t1/2,the peak concentration C_maxax and the area under the curve AUC_?0-t?have the corresponding increase tendency.4.The drug concentration measured in mice by inject is higher than i.g for signal.