Explore The Relationship Between Pharmacokinetics And Pharmacodynamics For Three Antihypertensive Drugs In Spontaneously Hypertensive Rats(SHR)

Objectives: The aims of this study was to investigate the relationships between thelevels of SBP, LVW／BW, renin activity, AngⅡand the level of exposure （pharmacokineticparameters AUC） in spontaneously hypertensive rats （SHR）， which were treated byEnalapril（Ena）, Benazepril （Bna）, Amlodipine（Aml） with different doses. Methods： theseSHR were randomly divided into ten groups： SHR-C（blank）,E2,E10,E25,B2,B10,B25,A3,A10,A25. SHRs were treated by relative antihypertensive drugsthrough Gastric perfusion method for7weeks．as well as the SHR-C（blank） were given thesame volume of distilled water．Blood pressure was measured in different experimentalphase，the weights of LV were calculated，the concentrations of renin activity and Ang Ⅱinplasma were detected by radioimmumity. Established the liquid chromatography-massspectrometry （LC-MS） method for determining the concentration of Enalapril （Ena）,Benazepril （Bna）, Amlodipine（Aml） in SHR plasma. determining the PK of the first and lasttime after continuous administration, calculated the pharmacokinetic/pharmacodynamics（PK/PD value）, At last, taking correlation analysis. Results: AUC of the three drugs did notchange significantly after continuous administration; In the Enalapril group, there was a linearrelationship between the MBP, LV/BW and the AUC changes, linear equations were: Y=0.256X+7.98（r=0.9595）, Y=0.3398X+4.5741（r-=0.9956）;which in the benazepril andamlodipine groups are not obvious. While, overall, with the increase in the level of exposure,the pharmacodynamics enhanced. Conclusion: AUC of the three drugs did not changesignificantly after continuous administration, which implied there is no significantrelationship between the antihypertensive effect and the AUC accumulation, theantihypertensive may be related with the action targets of the three drugs; In the Enalaprilgroup, there has a good linear relationship of MBP-AUC, LV/BW-AUC in the AUC changes(varied0-60μg L^-1 h), which can be used to predicate the pharmacodynamics based on theknown pharmacokinetics data.