Levine M A, Ogilvie R I, Leenen F H
Division of Clinical Pharmacology, Toronto, Western Hospital, Ontario, Canada.
Clin Pharmacol Ther. 1988 Jan;43(1):39-48. doi: 10.1038/clpt.1988.9.
The pharmacokinetic and pharmacodynamic effects of nisoldipine, a 1,4-dihydropyridine calcium entry blocker, and the lipophilic beta-adrenoceptor blocker propranolol were assessed alone and in combination in 12 healthy men. Oral nisoldipine, 20 mg, or placebo was followed 1 hour later by propranolol, 40 mg, or placebo using a randomized, crossover, double-blind design. Nisoldipine significantly increased the AUC (+43%) and peak plasma drug concentration (Cmax) (+68%) of propranolol resulting in a higher degree of beta-adrenoceptor blockade (as assessed by isoproterenol). Conversely, nisoldipine's AUC (+30%) and Cmax (+57%) were increased with concomitant administration of propranolol. Nisoldipine did not affect blood pressure but caused significant decrease in total peripheral resistance (TPR) and increases in plasma catecholamines and cardiac index. Forearm vascular resistance and blood flow changed more markedly than did TPR and cardiac index. In contrast, propranolol had little effect on forearm hemodynamics despite significant decreases in cardiac index and increases in TPR. The data are compatible with changes in hepatic blood flow, accounting for the pharmacokinetic interaction of nisoldipine and propranolol. Different vascular beds appear to contribute to the effects of nisoldipine vs. propranolol on peripheral resistance.
在12名健康男性中，单独及联合评估了1,4 - 二氢吡啶类钙通道阻滞剂尼索地平与亲脂性β肾上腺素受体阻滞剂普萘洛尔的药代动力学和药效学效应。采用随机、交叉、双盲设计，先口服20mg尼索地平或安慰剂，1小时后再口服40mg普萘洛尔或安慰剂。尼索地平显著增加了普萘洛尔的AUC（增加43%）和血浆药物峰浓度（Cmax，增加68%），导致更高程度的β肾上腺素受体阻滞（通过异丙肾上腺素评估）。相反，同时给予普萘洛尔时，尼索地平的AUC（增加30%）和Cmax（增加57%）也增加。尼索地平不影响血压，但导致总外周阻力（TPR）显著降低，血浆儿茶酚胺和心脏指数增加。前臂血管阻力和血流量的变化比TPR和心脏指数更明显。相比之下，普萘洛尔尽管使心脏指数显著降低且TPR增加，但对前臂血流动力学影响很小。这些数据与肝血流量的变化相符，解释了尼索地平和普萘洛尔的药代动力学相互作用。不同的血管床似乎对尼索地平与普萘洛尔对外周阻力的影响有所贡献。
