The effect of propranolol on paracetamol metabolism in man.

Ten healthy volunteers were treated for 4 days with 160 mg propranolol HCl and placebo in random order. At the end of each treatment salivary antipyrine kinetics and the plasma kinetics and urinary excretion of paracetamol and its major metabolites were measured following a 1500 mg oral dose. Propranolol prolonged the half-life of antipyrine by 11 +/- 5% (mean +/- s.e. mean) and lowered its clearance by 14 +/- 3% (P less than 0.05). Propranolol increased the half-life of paracetamol by 25 +/- 12% (P less than 0.05) and lowered its clearance by 14 +/- 3% (P less than 0.05). Propranolol decreased the partial clearance of paracetamol to its cysteine and mercapturate derivatives by 16 +/- 3% (P less than 0.05) and 32 +/- 7% (P less than 0.05), respectively. The partial clearance to the glucuronide conjugate was decreased by 27 +/- 6% (P less than 0.05), whereas that to sulphate was not changed significantly. Propranolol inhibits paracetamol metabolism predominantly through inhibition of the oxidation and glucuronidation pathways.     

Inhibition of antipyrine metabolism by beta-adrenoceptor antagonists.

1 The effects of two beta-adrenoceptor antagonists (propranolol and metoprolol), and of the beta-adrenoceptor agonist, terbutaline, on the plasma kinetics of antipyrine were studied in five normal subjects. In addition, the influence of propranolol on the clearance of antipyrine to three of its major metabolites was investigated. 2 At the same level of beta-adrenoceptor blockade, assessed by lowering of exercise tachycardia, propranolol decreased antipyrine clearance by 37.3 +/- 9.9 s.d. % (P less than 0.001) and metoprolol decreased it by 18.0 +/- 4.7 s.d. % (P less than 0.01). Terbutaline had no effect on antipyrine clearance. The volume of distribution of antipyrine was unchanged following treatment with all three drugs. 3 Only the metabolic clearance of antipyrine to its 3-hydroxymethyl product was impaired to a statistically significant degree by propranolol. However, four of the five subjects also showed impaired clearance to 4-hydroxyantipyrine and three of the five to norantipyrine after propranolol treatment. In four of the five subjects propranolol lowered the renal clearance of antipyrine. 4 Inhibition of the metabolism of antipyrine by beta-adrenoceptor antagonists may be related to their lipid-solubility and extent of metabolism and is independent of their effect on beta-adrenoreceptors.     

Do beta blockers differ in their effects on hepatic microsomal enzymes and liver blood flow?

The effects of three beta blockers on liver blood flow and hepatic enzyme activity were investigated. Eight healthy subjects received placebo, 100 mg metoprolol, 40 mg nadolol, and 60 mg propranolol orally three times a day for four days in a randomized block design. On the fourth day of each treatment, beta blockade was measured by inhibition of exercise-induced tachycardia and apparent liver blood flow was measured by indocyanine green clearance. Plasma concentrations of the beta blockers were measured 2 hours after the early morning dose. Metoprolol produced the greatest inhibition of exercise tachycardia. All three drugs appeared to reduce liver blood flow, but this was only statistically significant in the case of propranolol. Enzyme inhibition occurred but to a varying extent. Propranolol produced a 36 per cent fall in antipyrine clearance (P less than 0.1) while metoprolol and nadolol both caused a 12 per cent reduction (P less than 0.05 and P = 0.06, respectively). Wide interindividual variation in the plasma concentrations of the drugs limit interpretation, but the results suggest that at the doses used, metoprolol and nadolol may be less likely to cause significant drug interaction by enzyme inhibition than propranolol.     

Effect of lignocaine on arginine-vasopressin plasma levels: baseline or induced by frusemide.

1. To assess whether or not lignocaine influences baseline and frusemide-induced (5 mg kg-1) plasma concentrations of arginine-vasopressin (AVP), 2 groups of rabbits received an infusion of lignocaine (130 micrograms min-1 kg-1) for 6 h. Lignocaine-induced changes in AVP plasma concentrations were substantiated by measurement of diuresis and natriuresis and hepatic plasma flow, by means of an infusion of indocyanine green (ICG) (249 micrograms min-1 kg-1). 2. Baseline plasma AVP levels were 4.9 +/- 0.9 pg ml-1 (+/- s.e.), and following lignocaine, these values were reduced to 0.7 +/- 0.1 pg ml-1 (P less than 0.01). Frusemide increased AVP levels to 134.1 +/- 73.6 pg ml-1 (P less than 0.05) and lignocaine totally prevented this increase, e.g. mean AVP levels of 2.7 pg ml-1. 3. Lignocaine enhanced baseline diuresis secondary to an increase in free water clearance; none of the experimental conditions affected the diuresis and natriuresis induced by frusemide. 4. Frusemide reduced the hepatic plasma flow and this decrease was not reversed by the infusion of lignocaine. 5. It is concluded that in healthy rabbits lignocaine reduces baseline secretion of AVP and its antidiuretic effect; in addition, lignocaine prevents the rise in AVP induced by frusemide.     

Lignocaine and indocyanine green kinetics in patients following myocardial infarction.

1. Blood clearances of lignocaine and indocyanine green together with indocyanine green half-lives were measured in 17 post-myocardial infarct patients (one patient was studied twice) between 8 h and 36 h after starting intravenous lignocaine infusions for the treatment of cardiac arrhythmias. 2. Mean +/- s.d. values of lignocaine clearance (ml min-1 kg-1) were higher in patients without heart failure (11.8 +/- 2.6, n = 9) than in those with heart failure (7.2 +/- 1.9, n = 9) (P < 0002). 3. Clearances of lignocaine and indocyanine green were not correlated but lignocaine clearance was directly related to the reciprocal of indocyanine green half-life (rs = 0.67, P < 0.01). 4. In eight patients who received both lignocaine and indocyanine green and in a further five patients received only lignocaine and whose lignocaine infusions lasted 24h or more, a 25% rise in lignocaine concentrations was observed between 8-12h and 24-28h. 5. The mean +/- s.d. post-infusion terminal half-life of lignocaine in four patients whose lignocaine infusions lasted 30h or longer was 7.2 +/- 2.1 h. 6. Heart failure was associated with greater changes in lignocaine kinetics than in indocyanine green kinetics. 72% of the variance between observed and predicted lignocaine clearances could be accounted for by multiple linear regression analysis incorporating indocyanine green half-life and the presence or absence of heart failure. Indocyanine green half-life contributed only 17% of the variance indicating that by itself it is of limited value in predicting lignocaine requirements. 7. Lignocaine kinetics during and after prolonged intravenous infusion were not predicted by data obtained after intravenous bolus injection. 8. A lowering of lignocaine dosage may be clinically desirable in the presence of heart failure and if an infusion lasts longer than 24 h.     

The short term effects of propranolol, atenolol and labetalol on antipyrine kinetics in normal subjects.

1 The effects of three day courses of propranolol 40 mg three times daily, atenolol 100 mg twice daily and labetalol 100 mg three times daily on antipyrine kinetics were examined in 13 normal subjects. 2 The mean antipyrine clearance initially was 41.3 +/- 12.4 ml/min (mean +/- s.d.) and fell to 35.0 +/- 12.1 ml/min following propranolol (P less than 0.025), 34.5 +/- 9.5 ml/min following atenolol (P less than 0.01), and 35.2 +/- 8.6 ml/min following labetalol (P less than 0.05). 3 The prolongation in antipyrine half-life was significant only following atenolol. Propranolol only caused a significant reduction in the volume of distribution of antipyrine. 4 These adrenoceptor antagonists appear to decrease antipyrine clearance in normal subjects. The reduction in antipyrine clearance was similar with all three drugs and appeared to be independent of the differing lipid solubilities and pharmacological profiles of the adrenoceptor antagonists examined.     

Pharmacokinetics and effects of propranolol in terminal uraemic patients and in patients undergoing regular dialysis treatment.

Propranolol blood and plasma levels were measured after a single oral dose of 40 mg in patients with chronic renal failure, in patients undergoing regular dialysis treatment, and in healthy volunteers. Peak levels were observed in all cases within 1.5 to 3 hours. However, peak blood and plasma concentrations of propranolol in the chronic renal failure group were 2- to 3-fold higher (161 +/- 41 ng/ml) than those observed in the dialysis patients (47 +/- 9 ng/ml) and in the healthy volunteers (26 +/- 1 ng/ml). The apparent plasma clearance was also significantly reduced in the patients with chronic renal failure. The data suggest a reduced hepatic extraction in chronic renal failure patients. A significant increase in the fraction of the dose available to the systemic circulation was also found, together with a modification of apparent plasma half-life and volume of distribution in regular dialysis patients during the dialysis day as compared with the after-dialysis day. No extraction of propranolol by the dialyzer was noticed. Marked fluctuations in propranolol blood concentrations were also observed in patients on regular dialysis following continuous propranolol treatment. The suppressive effect of propranolol on plasma renin activity did not fully correlate with the hypotensive effect of the drug. On the basis of the reported data, propranolol should be used with great caution and at low doses in chronic renal failure.     

Penbutolol and propranolol: a comparison of their effects on antipyrine clearance in man.

The effects of two beta-adrenoceptor antagonists, penbutolol (administered on separate occasions as (+/-)- and (-)-forms) and propranolol, on the kinetics of antipyrine were studied in eight normal subjects. At the same degree of beta-adrenoceptor blockade, as assessed by the lowering of exercise tachycardia, propranolol decreased antipyrine clearance by 31 +/- 11 s.d.% (P less than 0.001) whereas neither of the two penbutolol formulations had a significant effect. The volume of distribution of antipyrine was unchanged following any of the beta-adrenoceptor antagonist treatments. The lack of effect of penbutolol on oxidative drug metabolism is not consistent with in vitro data suggesting a relationship between the lipid solubility of beta-adrenoceptor antagonists and inhibition of metabolism.     

Impaired elimination of propranolol due to right heart failure: drug clearance in the isolated liver and its relationship to intrinsic metabolic capacity.

It is unclear if reduced hepatic drug elimination in congestive heart failure is primarily due to impairment of enzyme function as a result of tissue hypoxia, to the direct effects of hepatic congestion, or to changes intrinsic to the liver, such as reductions in enzyme content and activity. We therefore compared propranolol clearance in perfused rat livers from animals with right ventricular failure (RVF) with that from control animals. Despite the fact that both groups were perfused at comparable flow rates, perfusion pressures, and levels of oxygen delivery, hepatic extraction of propranolol was significantly reduced in RVF livers (0.688 +/- 0.122 versus 0.991 +/- 0.006 ml/min/g of liver in controls, P <.001). This effect was reflected in a 97% reduction in propranolol intrinsic clearance in RVF livers (5 +/- 4 versus 172 +/- 82 ml/min/g of liver in controls, P <.01). In RVF livers, total hepatic CYP expression was reduced by 19% compared with controls, whereas cytochrome P450 isoenzymes 1A1/2 and 2D1 were reduced by 41 and 26%, respectively. Despite the 97% reduction in propranolol intrinsic clearance in perfused RVF liver, intrinsic clearance in microsomal preparations from the same livers was reduced by only 48% compared with controls (P <.05). These findings suggest that impaired propranolol clearance in RVF is not primarily accounted for by reduced hepatic oxygen delivery or by changes in hepatic content and activity of drug-metabolizing enzymes.     

(+)-Propranolol clearance, an estimation of hepatic blood flow in man

1 Hepatic blood flow was determined before and during (+)- and (+/-)-propranolol plasma concentration plateaus in 19 patients with suspected renal hypertension and normal liver function. 2 Hepatic blood flow significantly decreased (P less than 0.001) during (+/-)-propranolol administration and remained unchanged during (+)-propranolol administration. 3 Hepatic extraction ratio was 74 +/- 1% (+/-)-propranolol and 79 +/- 2% for (+)-propranolol. 4 Total propranolol clearances were determined during the steady-state achieved by a constant infusion. A highly significant positive relationship was observed (r = +0.86; P less than 0.01) between hepatic blood flow and (+)-propranolol clearance. The slope of the curve was 1.05 +/- 0.27. 5 The result implies that the total clearance of (+)-propranolol constitutes an accurate estimation of basal hepatic blood flow in subjects with normal liver function.     

Effects of lignocaine and propranolol on experimental cardiac arrhythmias

1. The effects of intravenous injection of lignocaine and propranolol were studied in dogs.2. Ventricular ectopic beats produced by intravenous injection of adrenaline in anaesthetized dogs respired with halothane were abolished in four out of six dogs by lignocaine. Propranolol was effective in all three dogs tested.3. Intravenous infusion of lignocaine at (0.2 and 1.0 mg/kg)/min to total doses of 3.0 +/- 1.0 and 2.2 +/- 0.5 mg/kg, respectively, abolished the ventricular tachycardia produced in anaesthetized dogs by ouabain. A similar effect was produced by infusion of propranolol at (0.2 mg/kg)/min to a total dose of 1.9 +/- 0.4 mg/kg. Intravenous injection of single doses of lignocaine (4.0-8.0 mg/kg) also abolished the arrhythmia.4. The frequency of the ventricular ectopic beats occurring in conscious dogs 20-44 h after ligation of the anterior descending branch of the left coronary artery was reduced, with an increase in the number of sinus beats, after intravenous injection of lignocaine (8.0 mg/kg). Larger doses produced excitement. Propranolol (4.0 mg/kg) had a greater effect than the same dose of lignocaine but after 8.0 mg/kg, three of the four dogs died.5. Propranolol was more effective than lignocaine in abolishing the three different types of arrhythmia.6. Dose-response curves showed that lignocaine was more active in abolishing the ouabain induced arrhythmia than the halothane-adrenaline arrhythmia and was least active on the arrhythmia caused by ligation of the coronary artery.     

Reduction of oral bioavailability of lignocaine by induction of first pass metabolism in epileptic patients.

1. The pharmacokinetics of lignocaine following single oral and intravenous doses have been investigated in six normal volunteers and in six patients receiving chronic antiepileptic drug therapy. 2. After intravenous administration, serum lignocaine levels declined biexponentially in all subjects. The serum clearance (mean +/- s.d.) was slightly higher in the patients (0.85 +/- 0.09 v 0.77 +/- 0.07 l/min) but the difference was not statistically significant. 3. Lignocaine bioavailability after oral administration was more than two-fold in the patients than in the normal subjects (0.15 +/- 0.06 v 0.37 +/- 0.09, P < 0.001). 4. It is suggested that the reduced bioavailability of lignocaine in the patients is a consequence of stimulation of hepatic first-pass metabolism by antiepileptic drugs.     

Assessment of hepatic blood flow in healthy subjects by continuous infusion of indocyanine green.

1. The applicability of a continuous infusion of indocyanine green (ICG) to detect changes in apparent hepatic blood flow (HBF) was investigated in six healthy subjects. 2. High-performance liquid chromatography was used to measure ICG concentrations, and the effect of intravenous propranolol (10 mg in 10 min) on HBF was investigated. 3. During 150 min infusions of ICG (1.0 mg min-1) steady-state was reached within about 30 min and thereafter the plasma dye concentration remained essentially constant until the end of infusion. 4. Blood clearance (CLb) of ICG (15.9 +/- 2.2 ml min-1 kg-1; mean +/- s.d.), calculated as infusion rate/blood dye concentration over three time periods (30-50, 80-100 and 130-150 min) during the 150 min infusion, was not different from that obtained with three 1-min infusions (0.5 mg kg-1) administered at corresponding times of the day (CLb = 14.0 +/- 2.2 ml min-1 kg-1, P = 0.06). 5. The pharmacokinetics of ICG were shown to be linear up to plasma concentrations of at least 3 micrograms ml-1 using variable infusion rates (0.5, 1.0 and 2.0 mg min-1). 6. Propranolol had little effect on ICG concentrations during continuous infusion. The AUC of ICG from the start of propranolol infusion up to 125 min thereafter was increased by 12% +/- 17% (P = 0.21) compared with placebo.     

Reduced hepatic uptake of propranolol in rats with acute renal failure

The effect of acute renal failure (ARF) on the hepatic uptake and metabolism of propranolol was investigated in relation to the hepatic clearance of the drug. ARF was induced by the subcutaneous injection of uranyl nitrate to rats. The uptake rate of propranolol in the isolated perfused liver was determined by the multiple-indicator dilution method and was found to decrease from 43.6 +/- 2.0 min-1 (mean +/- S.E.) in control to 29.4 +/- 1.7 min-1 in ARF (P less than 0.001). The recovery fraction of propranolol in effluent venous blood increased about twofold in ARF compared to control (P less than 0.05). The metabolic activity for propranolol was examined using the hepatic microsomal fraction prepared from control and ARF rats. There was no significant difference in the kinetics of oxidative metabolism of propranolol between two groups. These results suggest that the previously reported decrease in the hepatic clearance of propranolol in ARF is due to decreased hepatic uptake of the drug from the blood into the liver cells.     

Comparative pharmacokinetics of intravenous propranolol in obese and normal volunteers

Plasma pharmacokinetics of a single IV dl-propranolol dose (8 mg) were investigated in 12 obese subjects (mean +/- SD: 110.3 +/- 20.4 kg; 198.7 +/- 32.5% of ideal body weight) and compared with those of 12 healthy subjects (66.7 +/- 6.8 kg; 94.5 +/- 7.8% of ideal body weight). In obese subjects plasma alpha-1 glycoprotein acid concentrations and propranolol protein binding capacity did not differ significantly from control subjects. When compared with controls, obese subjects showed a significant increase (P less than .01) in AUC (161.0 +/- 67.0 vs 109.6 +/- 23.1 hr.micrograms/L), and significant decreases (P less than .01) in Vss (208.9 +/- 71.9 vs 318.6 +/- 91.8 L), V beta (234.3 +/- 70.4 vs 340.7 +/- 89.1 L), and total clearance (57.5 +/- 18.3 vs 75.9 +/- 15.4 L/hr). Elimination half-life was similar for the two populations (3.5 +/- 0.9 hr in obese subjects vs 3.1 +/- 0.9 hr in controls). Therefore, neither lipophilicity of propranolol nor drug plasma protein binding can explain these data. Altered hepatic function and tissue blood flow in obese subjects are proposed as an explanation for the decrease in total clearance and volume of distribution.     

The effect of beta-adrenoceptor antagonists on the pharmacokinetics and pharmacodynamics of warfarin after a single dose.

The effects of three beta-adrenoceptor antagonists (propranolol, metoprolol and atenolol) on the serum kinetics and pharmacodynamics of warfarin given in a single oral dose (15 mg) were studied in six normal subjects. At the same degree of beta-adrenoceptor blockade, as assessed by the decrease of exercise tachycardia, propranolol increased the area under the serum warfarin concentration time curve (AUC) by 16.3 +/- 14.2 s.d.% (P less than 0.01) and the maximum serum warfarin concentration by 23.0 +/- 14.3 s.d.% (P less than 0.001). Atenolol increased the maximum serum warfarin concentration by 12.5 +/- 12.3% s.d. (P less than 0.05) but was without effect on warfarin AUC. Metoprolol had no effect on warfarin kinetics. The extent of changes in the prothrombin time and the plasma clotting Factor VII activity caused by warfarin were not altered by any of the beta-adrenoceptor antagonists.     

The distribution of propranolol, pindolol and atenolol between human erythrocytes and plasma.

1 This study aimed (1) to measure the whole blood to plasma (WB:P) and red blood cell to plasma (RBC:P) concentration ratios of propranolol in healthy volunteers and two types of patients, and (2) to compare the concentration ratios of the lipophilic drug propranolol with moderately lipophilic pindolol and hydrophilic atenolol. 2 There was no significant difference between the WB:P and RBC:P ratios of propranolol concentration in healthy volunteers and neurological patients compared with hypertensive patients. The mean +/- s.d. WB:P ratios of propranolol concentration in the three groups were 0.74 +/- 0.03, 0.71 +/- 0.05, and 0.76 +/- 0.08 respectively. The mean RBC:P ratios were 0.39 +/- 0.08, 0.36 +/- 0.11, and 0.47 +/- 0.15 respectively. WB:P and RBC:P concentration ratios of propranolol were linearly correlated with the free fraction of drug in plasma. Propranolol was 90% bound in plasma. 3 The mean WB:P and RBC:P ratios of pindolol in seven volunteers were 0.69 +/- 0.08 and 0.37 +/- 0.14 respectively. Pindolol was 71.4 +/- 8.6% bound to plasma proteins. The concentration of pindolol in the RBC was linearly correlated with that unbound in plasma. 4 In four healthy volunteers, the mean WB:P concentration ratio of atenolol was 1.07 +/- 0.25 and the mean RBC:P ratio was 1.15 +/- 0.55. 5 The similarity of the RBC:free plasma drug concentration ratios for all three drugs suggests that the use of organic solvent partition coefficients for the prediction of in vivo distribution may be unreliable.     

Propranolol disposition in renal failure.

1 Previous studies of propranolol disposition in renal failure have been conflicting. 2 Using simultaneous administration of [3H]-propranolol intravenously and unlabelled propranolol orally the principal determinants of drug distribution were calculated in normals, patients with severe renal impairment (creatinine clearance 14.5 +/- 2.8 ml/min) but not on haemodialysis and patients on haemodialysis (creatinine clearance less than 5 ml/min). 3 The effect of haemodialysis on propranolol binding and free fraction was also examined. The percentage of propranolol unbound rose from 7.1% to 9.9%. (P less than 0.001) 20 min following heparinization and beginning haemodialysis. This was accompanied by a large rise in free fatty acids from 0.567 +/- 0.059 to 3.326 +/- 0.691 mumol/ml (P less than 0.005). 4 The blood to plasma concentration ratios of propranolol were significantly higher in patients with renal failure (P less than 0.02) and on haemodialysis (P less than 0.001) and were significantly negatively correlated (P less than 0.001) with the haematocrit. 5 Although the half-life propranolol was significantly shortened in the patients with renal failure (P less than 0.02), there was no change in the apparent liver blood flow, extraction ratio or the principal determinants of steady-state drug concentrations in blood namely oral and intravenous clearance from blood. 6 There is, therefore, no pharmacokinetic basis to adjust the dosage of propranolol in patients with renal failure.     

Haemodynamic effects of molsidomine and propranolol in patients with cirrhosis

Propranolol and molsidomine have both been shown to decrease the hepatic venous pressure gradient in patients with cirrhosis. The present study aimed at assessing the effects of the combination of these two drugs on splanchnic and systemic haemodynamics of cirrhotic patients. Fifteen patients with biopsy proven alcoholic cirrhosis had haemodynamic measurements under basal conditions, 60  min after oral administration of 4  mg molsidomine then 15  min after intravenous administration of 15  mg propranolol. As compared with baseline values, molsidomine was found to decrease mean arterial pressure (−7.9%, P <0.01), cardiac output (−7.3%, P <0.01), pulmonary wedged pressure (−45.8%, P <0.05) and hepatic venous pressure gradient (−11.7%, P <0.01). Propranolol decreased heart rate (−21%, P <0.01), further decreased cardiac output (−20.6%, P <0.01) and hepatic venous pressure gradient (−10.5%, P <0.01). As a whole, molsidomine plus propranolol decreased mean arterial pressure (−8%, P <0.01), heart rate (−19%, P <0.01), cardiac output (−26.5%, P <0.01) and hepatic venous pressure gradient (−21%, P <0.01). Pulmonary wedged pressure, liver blood flow and hepatic intrinsic clearance of indocyanine green were not significantly changed by the association of molsidomine and propranolol. We conclude that in patients with cirrhosis, molsidomine and propranolol potentiate their effects on hepatic venous pressure gradient. Such a combination could therefore prove useful in the treatment of portal hypertension.     

Pharmacokinetics and metabolism of the pharmacologically active 4'-hydroxylated metabolite of propranolol in the dog

The disposition of 4'-hydroxypropranolol (HOP) was determined after iv administration to dogs (2 mg/kg; N = 5) and the pharmacokinetic parameters were calculated from plasma measurements. The clearance of HOP, 66 +/- 6 ml/min/kg (mean +/- SE), was considerably higher than that of propranolol previously determined, suggesting extrahepatic as well as hepatic clearance of HOP. The plasma half-life of HOP, 77 +/- 6 min, was shorter than that of propranolol. Although HOP is considerably less lipophilic than propranolol, its volume of distribution, 6.4 +/- 0.8 liter/kg, surprisingly, was larger. Like propranolol, HOP appeared to be cleared entirely by metabolism. Whereas propranolol is metabolized mainly by oxidation, HOP was metabolized to sulfate (HOPS) and glucuronic acid (HOPG) conjugates. The plasma half-lives of these conjugates were 2 to 3 times longer than for HOP, reflecting a slow, continuous formation from HOP. This was established for HOPS by iv administration of synthetic HOPS. Morover, after HOP administration both formation and renal clearance of HOPS were stereoselective in favor of the R-enantiomer. In summary, the main conclusion of this study is that the large volume of distribution as well as high clearance through sulfation and glucuronidation may explain the low plasma HOP levels observed during propranolol therapy.