Zhou H H, Anthony L B, Roden D M, Wood A J
Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232.
Clin Pharmacol Ther. 1990 Jun;47(6):686-93. doi: 10.1038/clpt.1990.94.
Because both quinidine and propranolol bind to the cytochrome P-450 responsible for the oxidation of debrisoquin, six healthy male subjects were studied to determine whether an interaction occurred between the two drugs and the pharmacodynamic consequences of that interaction. The coadministration of quinidine resulted in a doubling of the area under the plasma concentration-time curve of (+/-)-propranolol (530 +/- 99 versus 1051 +/- 138 ng.hr/ml; p less than 0.05) and a reduction in the clearance of (+/-)-propranolol from 3087 +/- 648 to 1378 +/- 173 ml/min (p less than 0.05). The metabolism of propranolol by the 4-hydroxylation pathway was almost abolished by quinidine, resulting in a fall in the partial metabolic clearance by this pathway from 678 +/- 246 to 56 +/- 11 ml/min (p less than 0.05). Quinidine differentially affected the metabolism of (+)-propranolol and (-)-propranolol, resulting in an increase of 176.6% +/- 45.5% and 100.4% +/- 25.5% in the area under the plasma concentration-time curve of (+)-propranolol and (-)-propranolol, respectively (p less than 0.05). The pharmacokinetic changes were associated with pharmacodynamic effects. The combination of propranolol and quinidine resulted in increased beta-blockade measured by reduction in exercise heart rate and prolongation of the QTc and PR intervals. We conclude that quinidine stereoselectively inhibits the metabolism of propranolol through inhibition of the debrisoquin isozyme. The increased concentration of propranolol produced by quinidine results in increased beta-blockade.
由于奎尼丁和普萘洛尔均与负责异喹胍氧化的细胞色素P - 450结合，因此对6名健康男性受试者进行了研究，以确定这两种药物之间是否存在相互作用以及该相互作用的药效学后果。联合使用奎尼丁导致（±）-普萘洛尔血浆浓度 - 时间曲线下面积加倍（530±99对1051±138 ng·hr/ml；p<0.05），且（±）-普萘洛尔清除率从3087±648降至1378±173 ml/min（p<0.05）。奎尼丁几乎完全抑制了普萘洛尔通过4 - 羟基化途径的代谢，导致该途径的部分代谢清除率从678±246降至56±11 ml/min（p<0.05）。奎尼丁对（+）-普萘洛尔和（-）-普萘洛尔的代谢有不同影响，导致（+）-普萘洛尔和（-）-普萘洛尔血浆浓度 - 时间曲线下面积分别增加176.6%±45.5%和100.4%±25.5%（p<0.05）。药代动力学变化与药效学效应相关。普萘洛尔和奎尼丁联合使用导致通过运动心率降低以及QTc和PR间期延长所测得的β受体阻滞作用增强。我们得出结论，奎尼丁通过抑制异喹胍同工酶立体选择性地抑制普萘洛尔的代谢。奎尼丁使普萘洛尔浓度升高，导致β受体阻滞作用增强。
