ISSN:
1432-1041
Keywords:
propranolol
;
hepatic drug disposition
;
rat liver perfusion
;
pharmacokinetics in man
;
heart rate
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
,
Medicine
Notes:
Summary Studies were conducted to determine the mechanism whereby ethanol alters the hepatic disposition of propranolol. In eight isolated perfused rat livers, ethanol ( $$\bar x$$ =40.1 mmol/l diminished the clearance of dl-propranolol (1.93±0.43 to 1.24±0.22 ml/min/g liver, p〈0.05); increased its t1/2 (12.8±1.5 to 20.7±3.25 min, p〈0.01); and decreased the proportion metabolized (68.7±4.7% to 34.3±10.3%, p〈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〈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 ( $$\bar x$$ =0.090 vs 0.084) (p〈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〈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 off-set by the cardio-acceleratory effect of ethanol.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00544047
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