Dorian P, Sellers E M, Kaplan H L, Carruthers G, Hamilton C, Khouw V
Eur J Clin Pharmacol. 1984;27(2):209-15. doi: 10.1007/BF00544047.
Studies were conducted to determine the mechanism whereby ethanol alters the hepatic disposition of propranolol. In eight isolated perfused rat livers, ethanol (mean = 40.1 mmol/l diminished the clearance of dl-propranolol (1.93 +/- 0.43 to 1.24 +/- 0.22 ml/min/g liver, p less than 0.05); increased its t1/2 (12.8 +/- 1.5 to 20.7 +/- 3.25 min, p less than 0.01); and decreased the proportion metabolized (68.7 +/- 4.7% to 34.3 +/- 10.3%, p less than 0.01). These results suggest that ethanol could substantially increase the oral bioavailability of propranolol in humans. However, in normal human volunteers administered 80 mg of propranolol orally, alone, or preceded and followed by ethanol to maintain breath ethanol concentrations of 800-1000 mg/l, increases in propranolol AUC were smaller than anticipated. Seven subjects had increases in free propranolol AUC0-8h (32%, range: 12-61%) (p less than 0.05), while total propranolol AUC0-8h increased by a mean 22% (range: -4-+49%). Propranolol free fraction varied with time and was higher after ethanol (mean = 0.090 vs 0.084) (p less than 0.077). The extent of the propranolol-induced slowing of heart rate was not influenced by ethanol (mean decrease from baseline of 13 bpm at peak propranolol effect vs 9 bpm without ethanol); mean heart rates following propranolol with ethanol were higher at all times (mean of 7.5 bpm) (p less than 0.001) than after propranolol alone. Ethanol inhibits the hepatic oxidative metabolism of propranolol in vitro; however, any effect on heart rate of higher concentrations of propranolol induced by ethanol in humans is offset by the cardio-acceleratory effect of ethanol.
开展了多项研究以确定乙醇改变普萘洛尔肝脏处置过程的机制。在8个离体灌注大鼠肝脏中，乙醇（平均浓度 = 40.1 mmol/l）降低了消旋普萘洛尔的清除率（从1.93±0.43降至1.24±0.22 ml/min/g肝脏，p<0.05）；延长了其半衰期（从12.8±1.5增至20.7±3.25分钟，p<0.01）；并降低了代谢比例（从68.7±4.7%降至34.3±10.3%，p<0.01）。这些结果表明乙醇可能会大幅增加普萘洛尔在人体中的口服生物利用度。然而，在正常人类志愿者中，单独口服80 mg普萘洛尔，或在服用普萘洛尔前后饮用乙醇以维持呼气乙醇浓度在800 - 1000 mg/l，普萘洛尔曲线下面积（AUC）的增加幅度小于预期。7名受试者游离普萘洛尔AUC0 - 8h增加（32%，范围：12% - 61%）（p<0.05），而总普萘洛尔AUC0 - 8h平均增加22%（范围：-4% - +49%）。普萘洛尔的游离分数随时间变化，乙醇作用后更高（平均值分别为0.090和0.084）（p<0.077）。普萘洛尔引起的心率减慢程度不受乙醇影响（普萘洛尔效应峰值时心率从基线平均降低13次/分钟，未用乙醇时为9次/分钟）；服用普萘洛尔后同时饮用乙醇时的平均心率在所有时间都更高（平均高7.5次/分钟）（p<0.001），高于单独服用普萘洛尔后。乙醇在体外抑制普萘洛尔的肝脏氧化代谢；然而，乙醇在人体中引起的较高浓度普萘洛尔对心率的任何影响都被乙醇的心脏加速效应所抵消。
