急性心肌缺血对原儿茶醛在大鼠体内药动学的影响

Effect of acute myocardial ischemia on pharmacokinetics of protocatechuic aldehyde in rats

结扎大鼠冠状动脉左前降支造成急性心肌缺血模型。4h后,模型组大鼠和正常组大鼠分别腹腔注射原儿茶醛(20mg/kg),在不同时间点眼眶采血。用HPLC方法测定血浆中原儿茶醛及其代谢物原儿茶酸和香草酸的浓度,并对实验数据进行分析,从代谢角度考察急性心肌缺血对原儿茶醛在大鼠体内药动学的影响。结果表明,原儿茶醛在大鼠体内迅速代谢为原儿茶酸,后者甲基化代谢生成香草酸。与正常状态相比,急性缺血状态下原儿茶酸的AUC0-∞显著增大(22.31±4.96μg.h/mLvs14.01±3.11μg.h/mL,P<0.01);香草酸的AUC0-∞也显著增大(38.76±5.75μg.h/mLvs19.64±4.36μg.h/mL,P<0.01);两者的MRT均显著增加,分别为:0.43±0.08hvs0.27±0.04h(P<0.01);0.61±0.11hvs0.38±0.05h(P<0.01)。原儿茶酸甲基化代谢比率M/P明显提高(1.77±0.22vs1.43±0.31,P<0.05)。提示急性心肌缺血状态下,原儿茶醛的主要代谢物原儿茶酸和香草酸在血浆中的暴露显著增强,原儿茶酸甲基化生成香草酸的水平明显提高。

Acute myocardial ischemia （AMI） was induced by occlusion of the left anterior descending （LAD） coronary artery in rats. AMI rats and normal rats were administered with protocatechuic aldehyde（Pal） at a single dose of 20 mg/kg through peritoneal injection.Concentrations of Pal,protocatechuic acid （PAC） and vanillic acid （VAC） in plasma were determined by HPLC to evaluate the effect of AMI on pharmacokinetics of Pal in rats.Pal was quickly metabolized to PAC,which was then methylated into VAC.Compared to the normal group,AUC0-∞ of PAC significantly increased from 14.01±3.11 to 22.31±4.96 μg·h/mL in AMI group （P〈0.01）,and AUC0-∞ of VAC markedly elevated from 19.64±4.36 to 38.76±5.75 μg·h/mL （P〈0.01）.Both MRT of PAC and VAC increased （0.43±0.08 h vs 0.27±0.04 h,0.61±0.11 h vs 0.38±0.05 h,P〈0.01）.Metabolic ratio M/P of PAC increased from 1.43±0.31 to 1.77±0.22 （P〈0.05）.Results indicated that AMI status had great influence on pharmacokinetic behavior of Pal.Meanwhile,the level of methylation was greatly increased.