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Five healthy male volunteers ingested 40 mg of propranolol in the morning and the blood plasma was analyzed at various intervals by gas chromatography and mass spectrometry. In addition to propranolol, its metabolites 4-OH propranolol, 4-OH propranolol glucuronide and propranolol glucuronide, were found in the plasma. The plasma concentrations of these substances reached maximum levels 2-3 hours after propranolol ingestion. The ratio of propranolol over 4-OH propranolol, (U), and also the ratio of propranolol plus propranolol glucuronide over 4-OH propranolol plus 4-OH propranolol glucuronide (U + G), were calculated. The area under the concentration-time curves (AUC) of these compounds were calculated over 8 hours and the AUC0-8 hr ratios were computed for both (U) and (U + G). The AUC0-8 hr ratio was, in both (U) and (U + G) ratios, linearly correlated with the ratio obtained 2 hours after the propranolol ingestion. Accordingly, the 2-hour values of the (U) or (U + G) ratios were thought to represent the metabolic ratio of the propranolol hydroxylation, and the distribution of these ratios was examined in 162 healthy young male volunteers. Based on the null hypothesis theory, 4 out of the 162 volunteers (2.5%) were judged as poor metabolizers of the debrisoquine-type, ie, hydroxylation of propranolol. The pulse rate, systolic blood pressure and intraocular pressure decreased after propranolol ingestion, the maximum effects being at 2-3 hours after the ingestion. No significant effect was found on the diastolic blood pressure. In the subjects with poor propranolol metabolism, the pharmacological effects of propranolol did not differ significantly from those in other subjects.
The kinetics of propranolol enantiomers are stereoselective when high doses of the racemic drug are given po. To document whether the dose and/or the route of administration determines the stereoselective kinetics of propranolol enantiomers, conscious rabbits received 40, 80, or 120 mg/kg po or 0.5 or 10 mg/kg iv doses of racemic propranolol, and serial blood samples were obtained to assay propranolol enantiomers. At low po and iv doses, the kinetics of the propranolol enantiomers were identical. After the 120 mg/kg po dose, the kinetics of the enantiomers were stereoselective, i.e. the AUC0-->infinity for (S)-(-)-propranolol was greater than the AUC0-->infinity for (R)-(+)-propranolol (p < 0.05). The iv injection of 10 mg/kg generated zero-order kinetics, and (S)-(-)-propranolol was eliminated faster than the antipode. Propranolol enantiomer plasma protein binding was not stereoselective. In vitro, after the incubation of 5.8 or 58 microM (RS)-propranolol with cells of the intestinal mucosa or the liver, (R)-(+)-propranolol was more rapidly metabolized than (S)-(-)-propranolol at both concentrations in the intestine and at the higher concentration in the liver. Incubation of the individual enantiomers (2.9 and 29 microM) showed that in the intestine the intrinsic clearance of (R)-(+)-propranolol was greater than that of (S)-(-)-propranolol but in the liver there was preferential saturation of (S)-(-)-propranolol clearance. In conclusion, at low po or iv doses the kinetics of (RS)-propranolol are not stereoselective because the liver overshadows the effect of the intestine, and at high po doses the kinetics of propranolol enantiomers are stereoselective because of hepatic saturation of (S)-(-)-propranolol clearance.
Propranolol, a nonselective beta-adrenergic blocker, has been shown to reduce portal pressure and the risk fo variceal bleeding. The portal pressure-reducing effect of propranolol is mediated by splanchnic arterial constriction, which decreases portal flow. A double-blind randomized control study (crossover on 2 consecutive days) was designed to compare the effects of propranolol vs. placebo on portal flow in cirrhotic patients during fasting and after a standardized meal. Portal flow was measured with an ATL Ultramark 8 echo-Doppler system (Advanced Technological Laboratories, Bothel, WA) in 23 cirrhotic patients. Fasting portal flow and heart rate were obtained at baseline and 2 hours after the administration of propranolol or placebo. A standard test meal was then given, and measurements were repeated 30 minutes later. Thirteen patients (group 1) received placebo on day 1 and propranolol on day 2, whereas 10 patients (group 2) received propranolol on day 1 and placebo on day 2. In group 1 patients, heart rate declined by 20% (P less than 0.0001) and portal flow decreased by 12% (P less than 0.05) after propranolol administration. Similar reductions were found in heart rate (-21%, P less than 0.0001) and portal flow (-17%, P less than 0.001) for group 2 patients. For all 23 patients, 2 hours after propranolol administration, heart rate declined by 21% (P less than 0.0001) and portal blood flow was reduced by 14% (P less than 0.0001). The 10 patients who received propranolol on day 1 (group 2) showed a carryover effect of propranolol on day 2. On day 2, baseline portal flow and heart rate values were significantly lower than baseline values on day 1. This long-lasting effect of a single dose of propranolol may be caused by the longer half-life of propranolol in cirrhotic patients. The postprandial portal blood flow percentage increase after the meal was similar for both placebo and propranolol. Propranolol did not blunt postprandial hyperemia. However, whereas the absolute value of blood flow after the meal increased significantly in comparison with baseline in placebo-treated patients (P less than 0.001), this did not occur with propranolol. Furthermore, in propranolol-treated patients the absolute value of blood flow after the meal was lower than in placebo-treated patients. This may constitute a protective effect of propranolol in portal hypertension.
Our aim was to determine possible stereoselectivity in the plasma binding of propranolol. Equilibrium dialysis with plasma from seven healthy subjects and a deuterium-labeled pseudoracemate of propranolol was used. Plasma binding of the propranolol enantiomers differed with the unbound fraction of (-)-propranolol (22 +/- 2%; mean +/- SE) being smaller than that of (+)-propranolol (25.3 +/- 1.9%). The (-)/(+)-propranolol ratio for the unbound fraction, a measure of the stereoselectivity, was 0.86 +/- 0.02. There was an inverse correlation between the unbound (-)/(+)-propranolol ratio in individual subjects and overall binding of (+/-)-propranolol, indicating greater stereoselectivity at higher total binding. To assess the site of the stereoselective binding to plasma proteins, the binding of (+)- and (-)-propranolol to human alpha 1-acid glycoprotein (AGP) and human serum albumin (HSA) was examined. The binding to AGP was stereoselective for (-)-propranolol with a (-)/(+)-propranolol ratio for the unbound fraction of 0.79 +/- 0.01, whereas (+)-propranolol was bound to a greater extent to HSA with a (-)/(+)-propranolol ratio for the unbound fraction of 1.07 +/- 0.01. Although these results demonstrate opposite stereoselectivity in the binding of (+)- and (-)-propranolol to AGP and HSA, the stereoselective binding of (-)-propranolol to AGP predominates in plasma. This stereoselective plasma binding of the (-)-enantiomer of propranolol could limit the access of this more active enantiomer to beta-receptors or other active sites. The uptake of propranolol by red blood cells was not stereoselective.