Pharmacokinetics And Tissue Distribution Of Matrine In Isoproterenol-induced Acute And Chronic Cardiac Hypertrophy Rats

ObjectiveCardiac hypertrophy is common in clinical practice,matrine has a protective effect on the heart.Based on the previous experiment,in this paper,we established the acute and chronic cardiac hypertrophy rat model which is induced by isoproterenol,and study on the pharmacokinetic and tissue distribution changes of matrine in isoproterenol（ISO）-induced different degrees of cardiac hypertrophy rats.Methods1 To establish and assess the model of rat acute and chronic cardiac hypertrophyEstablished model of rat acute and chronic cardiac hypertrophy model induced by ISO,observed the common situation of rats,obtained the cardiac structure and function parameters by echocardiography and dissected the heart and scales,calculate the index of heart weight/body weight（HW/BW）.2 Pharmacokinetic study of matrine on rat cardiac hypertrophy modelEstablished model of rat acute and chronic cardiac hypertrophy model induced by ISO,matrine was intragastrically（ig）offered to each rat,blood samples for the PK assessment were taken and kept until the analysis at the different time.On the basis of the FDA Guidance for Industry Bioanalytical Method Validation,established method of HPLC-MS/MS to determine the plasma and tissue matrine concentrations.Observed the matrine pharmacokinetic（PK）variation in rat acute and chronic cardiac hypertrophy model induced by ISO.3 Tissue and distribution study of matrine on rat cardiac hypertrophy modelEstablished model of rat acute and chronic cardiac hypertrophy model induced by ISO,according to the PK characters,after the matrine intragastrically（ig）treated to each rat.,Choose a point in time respectively at absorption phase,distribution phase and elimination phase,tissue samples（heart,liver,spleen,lung,kidney and brain）were taken from rats,and kept until the analysis after treatment.Investigated the matrine tissue distribution condition in rat acute and chronic cardiac hypertrophy model induced by ISO.Results1 To establish and assess the model of rat acute and chronic cardiac hypertrophyEchocardiogram showed that the left ventricular anterior wall thickness（LVAWT）and left ventricular posterior wall thickness（LVPWT）in the acute cardiac hypertrophy model were significantly different from those in the control（P<0.01）,while there were no marked differences between the two groups in the left ventricular end-diastolic diameter（LVEDD）,left ventricular end-systolic diameter（LVESD）,ejection fraction（EF）and fractional shortening（FS）（P>0.05）.However,the LVAWT,LVPWT and LVESD in the chronic cardiac hypertrophy model were remarkably increased compared with those in the HCGR（P<0.01）,but the LVEDD did not dramatically altered（P>0.05）,in addition,the EF and FS were noticeably reduced（P<0.01）.2 Pharmacokinetic study of matrine on rat cardiac hypertrophy modelThe calibration curve of matrine was linear in the range of 10-3000 ng·mL^-1 in rat plasma and tissues and its lower limit of quantitation（LLOQ）was 10 ng·mL^-1.The inter-and intra-day RSDs were all less than 15% and extraction recovery rate was 78.4 ± 11.0%.There were no differences in the pharmacokinetic parameters of matrine between the control and acute cardiac hypertrophy model,while the maximum concentration（Cmax）,time to the maximum concentration（Tmax）and area under the curve（AUC）of the chronic cardiac hypertrophy model were significantly expanded in comparison of the control（P<0.01）;nevertheless,its plasma clearance（Cl）was evidently decreased（P<0.01）.Compared with the acute cardiac hypertrophy model,the AUC and Cmax were augmented,and the Cl decreased in the chronic cardiac hypertrophy model.3 Tissue and distribution study of matrine on rat cardiac hypertrophy modelAfter matrine was orally administered,the content of in rat tissue was in turn the liver,kidney,spleen,lung,brain and heart in healthy rats.In acute cardiac hypertrophy model were in turn the liver,kidney,spleen,lung,heart and brain.In chronic cardiac hypertrophy model were in turn the spleen,kidney,liver,lung,brain and heart.Liver,spleen and kidney were main distribution organ of matrine.At different stages of disease,observed tissue distribution has changes of matrine.ConclusionIt was found that pharmacokinetic profiles of matrine was not affected by acute compensatory cardiac hypertrophy,whereas chronic pathologic cardiac hypertrophy model was on the contrary.The exposure of matrine was enhanced and reduced the plasma clearance in the chronic pathologic cardiac hypertrophy rats.Tissue distribution showed concentration of matrine had some variation in the reversal of cardiac hypertrophy.