地尔硫䓬在离体豚鼠心脏中的药代动力学及动态效应
Pharmacokinetics and dynamic effects of diltiazem in the isolated guinea-pig heart.
作者信息
Jensen H K, Nielsen-Kudsk F
机构信息
Institute of Pharmacology, University of Aarhus, Denmark.
出版信息
Pharmacol Toxicol. 1988 Mar;62(3):166-71. doi: 10.1111/j.1600-0773.1988.tb01866.x.
Myocardial pharmacokinetics of diltiazem showed two-compartment characteristics in the isolated, spontaneously beating guinea-pig heart. Half-times of initial and terminal drug accumulation phases were about 2.1 and 14.4 min., respectively. At 1 microgram ml-1 (2.4 microM) in the perfusion liquid the average concentration of diltiazem in the myocardium at steady state was about 16 micrograms g-1 (38.6 microM) with 17% referable to the deepest, possibly intracellular compartment. Increasing diltiazem concentrations from 13 to 889 ng ml-1 (31-2144 nM) produced a progressive increase in coronary flowrate from 100 to 174%. The computed Em- and EC50-values were 73.2% and 187 nM, respectively. Oxygen consumption decreased to 27.6% showing Em = 106% and IC50 = 1536 nM. Amplitude and velocity of myocardial contraction decreased to about 6% and 2%; Em = 101% and 104%, IC50 = 266 and 186 nM, respectively. Heart beating frequency decreased to 63% exhibiting Em = 58% and IC50 = 2015 nM. The PQ- and QRS-intervals increased to 133% and 112%, respectively. The frequency-corrected QT-interval decreased to 81.6%. Our findings demonstrate a relatively rapid and moderate accumulation of diltiazem in the guinea-pig heart accompanied by a marked increase in coronary flow, progressive and pronounced negative inotropic and chronotropic effects and a less than proportional decrease in oxygen consumption.
在离体、自主跳动的豚鼠心脏中，地尔硫䓬的心肌药代动力学呈现双室特征。初始和终末药物蓄积相的半衰期分别约为2.1分钟和14.4分钟。在灌注液中浓度为1微克/毫升（2.4微摩尔）时，稳态下心机中地尔硫䓬的平均浓度约为16微克/克（38.6微摩尔），其中17%归因于最深层、可能是细胞内的室。将地尔硫䓬浓度从13纳克/毫升增加到889纳克/毫升（31 - 2144纳摩尔），可使冠状动脉血流速率从100%逐渐增加到174%。计算得出的Em和EC50值分别为73.2%和187纳摩尔。耗氧量降至27.6%，Em = 106%，IC50 = 1536纳摩尔。心肌收缩的幅度和速度分别降至约6%和2%；Em = 101%和104%，IC50分别为266纳摩尔和186纳摩尔。心率降至63%，Em = 58%，IC50 = 2015纳摩尔。PQ间期和QRS间期分别增加到133%和112%。经频率校正的QT间期降至81.6%。我们的研究结果表明，地尔硫䓬在豚鼠心脏中蓄积相对迅速且适中，同时伴有冠状动脉血流显著增加、进行性且明显的负性肌力和负性变时作用以及耗氧量小于成比例的降低。
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