SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Background

: The haemodynamic effect of propranolol on portal pressure in patients with portal hypertension is highly variable and does not correlate with propranolol racemate plasma concentrations.

Aim

: To investigate the stereoselective metabolism of the propranolol enantiomers and its impact on portal haemodynamics in patients with liver cirrhosis since only S-propranolol is haemodynamically active.

Methods

: Twenty patients with liver cirrhosis and portal hypertension received 40 mg propranolol orally. Portal blood velocity (PBV) and propranolol stereoisomer plasma concentrations were determined.

Results

: During the 4 h examination period we observed a significant reduction in PBV (18.3 ± 2.2%, < 0.0001) vs. baseline. The area under the curve (AUC) during the study period was significantly different for the two isomers (S-propranolol 1217.0 ± 118.5 nmol.h/L; R-propranolol 728.8 ± 103.8 nmol.h/L, < 0.0001). Seven patients (35%) were portal haemodynamic non-responders to propranolol. Propranolol stereoisomer AUC values were no different between responders (S-propranolol 1133.3 ± 132.0 nmol.h/L; R-propranolol 718.0 ± 129.7 nmol.h/L) and non-responders (S-propranolol 1371.8 ± 250.5 nmol.h/L; R-propranolol 746.9 ± 200.3 nmol.h/L); neither was there a correlation between propranolol enantiomer plasma concentrations and the portal haemodynamic effect.

Conclusions

: Our data demonstrate a stereoselective metabolism of propranolol enantiomers in liver cirrhosis. However, following oral propranolol administration, stereoisomer plasma concentrations do not predict the portal haemodynamic effect.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Propranolol, a non-selective beta-adrenoceptor antagonist, is the treatment of choice for primary prophylaxis of variceal bleeding. It also prevents rebleeding in patients with portal hypertension.1, 2 The blockade of both β1- and β2-adrenoceptors leads to a decrease in portal pressure by reducing cardiac output and by splanchnic vasoconstriction due to unopposed α-adrenergic activity.2[3][4][5]–6 Prospective studies have shown that a hepatic venous pressure gradient reduction of at least 20% or a drop below 12 mmHg should be the goal in order to achieve a clinically significant degree of reduction in bleeding risk.6[7]–8 Unfortunately, the pharmacological effects of propranolol on the portal haemodynamics vary greatly. At least one-third of patients do not respond adequately.9[10]–11 Numerous studies indicate that neither clinical nor systemic haemodynamic parameters (e.g. severity of liver disease, change in heart rate) can satisfactorily indicate the portal pressure response.4, 6, 9, 10, 12, 13 Thus, the measurement of portal haemodynamic parameters is necessary to assess the portal haemodynamic response to propranolol. Pulsed Doppler ultrasound has been established as a reliable and reproducible method for non-invasively assessing the acute effect of propranolol on portal haemodynamics in patients with liver cirrhosis.12

It is remarkable that total plasma propranolol levels do not correlate with the portal haemodynamic response.10 Propranolol is administered as a racemic mixture. However, the R-enantiomer is haemodynamically inactive.15[16]–17 Thus, a considerable proportion of the total plasma propranolol has no haemodynamic effect and may obscure the relationship between plasma concentrations and haemodynamic response because a linear correlation between the plasma concentrations of the active isomer (S-propranolol) and total propranolol has not been established. The hepatic metabolism of the two isomers is stereospecific in healthy subjects; R-propranolol is metabolized faster than S-propranolol, resulting in higher S-propranolol plasma levels.18 It has been shown for carvedilol that such a metabolic stereoselectivity can be greatly altered in patients with liver cirrhosis as compared to healthy subjects.19 These results have been substantiated in rats that underwent portacaval shunting.20 Certain studies have used R-propranolol as a model drug for investigating reduced hepatic drug clearance in patients with cirrhosis.21, 22 To date, however, no data exist on the stereoselectivity of the propranolol metabolism in patients with chronic liver disease. The bioavailability and the metabolism of the racemate are known to be considerably altered in liver cirrhosis,14 e.g. due to changes in the hepatic glucuronidation and oxidation, changes in protein binding or due to portosystemic shunting. If such changes affect the stereoselectivity of the propranolol metabolism, this could explain both the inter-individual differences in portal haemodynamic response to propranolol and the lack of correlation between total propranolol plasma levels and the effect on portal haemodynamics.

We therefore investigated the plasma concentrations of the haemodynamically active (S-propranolol) and inactive (R-propranolol) propranolol stereoisomers and correlated these levels with the changes in portal blood velocity in patients with liver cirrhosis and portal hypertension.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Patients

Twenty patients (Table 1) with liver cirrhosis and portal hypertension participated in this study after giving written informed consent. The diagnosis of liver cirrhosis was based on either liver biopsy or unequivocal clinical and biochemical findings. Patients received upper gastrointestinal endoscopy to assess portal hypertension and gastrointestinal bleeding risk. In all patients application of propranolol was indicated to prevent first or recurrent bleeding. In two patients with no oesophageal varices, propranolol was given to prevent recurrent bleeding due to severe hypertensive gastropathy. None of the patients had an established shunt. Treatment with beta-blockers or nitrovasodilators had not been given for at least 1 month before haemodynamic evaluation. Patients with systemic hypotension (systolic blood pressure < 100 mmHg), bradycardia (heart rate < 50/min), obstructive airway disease or other contraindications against propranolol treatment were excluded from the study.

Table 1.  . Clinical and biochemical characteristics of the patients enrolled in the study Thumbnail image of

Evaluation of portal haemodynamic response

Because recent studies have indicated that propranolol reduces portal blood flow (PBF) mainly by reducing the portal blood velocity (PBV), without changing the vessel’s diameter,12 PBV was assessed as a non-invasive parameter for the portal haemodynamics. B-mode duplex-sonographic PBV measurements (SSH-140 A, Toshiba, Tokyo, Japan) of all patients were carried out by a single observer in all patients. After identifying the portal vein from a subcostal approach, the transducer was placed on the longitudinal axis of the portal vein at its crossing point with the hepatic artery. Measurements were performed in triplicate at a < 60° Doppler angle; the Doppler sample volume was two-thirds of the vessel’s diameter. Patients showing a reduction in PBV of at least 20% over at least 1 h were defined as portal haemodynamic responders to propranolol.

Assessment of S- and R-propranolol plasma levels

The plasma propranolol levels of both enantiomers were determined by reversed-phase high performance liquid chromatography (HPLC) using pronethalol as an internal standard.23 The HPLC system consisted of an HPLC pump and a fluorescence detector (Shimadzu, Kyoto, Japan). The samples were injected onto the column using an auto-injector (Shimadzu, Kyoto, Japan). Conjugated propranolol was assayed with glucuronidase/sulphatase from helix pomatia (Boehringer, Mannheim, Germany). Sodium chloride (Merck, Darmstadt, Germany) was added to each sample to support the release of propranolol from plasma protein binding and the partial precipitation of the protein. Propranolol was extracted with dichloromethane (Baker-HPLC-grade, Mallinckrodt-Baker, Phillipsburg, NJ). After shaking the mixture was centrifuged. The organic layer was carefully transferred into a second test tube and evaporated at 40 °C under nitrogen. The residue was reconstituted in chloroform and triethylamine and R-(+)-phenyl-ethyl-isocyanate (R-PEIC) (Aldrich, Steinheim, Germany) was added for chiral derivatization. After incubation at ambient temperature, the tubes were evaporated once more at 40 °C under nitrogen. The residue was reconstituted with the mobile phase and injected onto the column. The separation of both propranolol stereoisomers was performed on an EC-Column (EC 125/4,6 Nucleosil 100-5 C18, length 125 mm, ID 4.6 mm) with a pre-column (KS 11/4 Nucleosil 100-5 C18 AB, length 11 mm, ID 4 mm). The liquid phase was a mixture of methanol/water (68:32 v/v) and was delivered isocratically by a constant flow rate of 1.2 mL/min. For both stereoisomers the limit of detection was 7.72 nmol/L and the limit of quantification was 15.44 nmol/L. The coefficient of variation was < 10% when 10 samples of the same propranolol concentration were measured (overall reproducibility). The within-run precision was 6%.

During the 4 h of haemodynamic evaluation following drug administration, areas under the curve for both S- and R-propranolol (AUC0–4 h) were calculated by linear trapezoidal rule.

Study design

The patients were examined in a supine position starting at 09.00 hours, following an overnight fast. After a 60 min period at rest, stable baseline values of heart rate (HR), blood pressure and PBV were obtained. Each patient then received one 40 mg tablet of propranolol (Dociton; Zeneca, Plankstadt, Germany). Peripheral venous blood samples for the determination of plasma S- and R-propranolol concentrations were drawn at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6 and 24 h after drug administration in heparinized tubes via an indwelling catheter. Blood samples were immediately centrifuged and the plasma frozen at – 20 °C. HR was monitored continuously; systolic and diastolic blood pressure were registered at 5 min intervals. PBV was measured every 30 min for 4 h following drug administration. All haemodynamic effects during this 4 h study period were calculated as mean changes and compared to baseline levels for correlation with S-propranolol (AUC0–4 h).

The study was performed according to the 1975 Declaration of Helsinki. The study protocol was approved by the ethical committee of the University of Bonn, Germany.

Statistical analysis

Results are expressed as mean ± standard error of the mean (s.e.). Differences between groups were analysed using Fisher’s exact test and the unpaired Student’s t-test. Haemodynamic effects were compared by analysis of variance for repeated measurements and paired or unpaired Student’s t-test, as appropriate. The non-parametric Mann–Whitney U-test was used to compare propranolol AUCs between groups. Statistical significance of correlation analysis was calculated by the Pearson correlation test. A two-tailed P-value below 0.05 was considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Haemodynamic response

The acute effect of 40 mg propranolol per os on PBV is illustrated in Figure 1. Overall, PBV exhibited a significant reduction, beginning only 30 min after drug administration with a maximum effect after 2.5 h (0.192 ± 0.0093 m/s at baseline vs. 0.137 ± 0.012 m/s averaged during the 4 h following drug administration, < 0.001). After 3 h, PBV showed a tendency to increase.

image

Figure 1. . Portal blood velocity (mean ± s.e.) after one oral dose of 40 mg propranolol racemate.

Download figure to PowerPoint

Although a significant drop in PBV was observed within the whole group according to the noted definition, seven (35%) out of the 20 patients did not respond adequately. As illustrated in Table 2, the group of propranolol responders showed a highly significant decrease in PBV and HR and a borderline significant decrease in MAP. In contrast, the group of non-responders showed only a significant reduction in HR (< 0.001) and a slight reduction in PBV (< 0.05), whereas the MAP remained unchanged (Table 2).

Table 2.  .  Haemodynamic effects of an oral load of 40 mg propranolol racemate Thumbnail image of

None of the clinical and biochemical parameters listed in Table 1 was significantly different between responders and non-responders, nor were baseline values for HR and PBV (Table 2). Mean arterial pressure was significantly higher in the non-responders compared to the responders (96.7 ± 4.7 mmHg vs. 84.9 ± 2.3 mmHg, < 0.05), but mean PBV reduction during the study period did not correlate with HR reduction (r=0.08) or with MAP reduction (r=0.24).

S- and R-propranolol plasma concentrations

After oral administration of the 40 mg racemic drug, maximum S-propranolol plasma concentrations (462.0 ± 44.4 nmol/L) were significantly higher than those of R-propranolol (311.5 ± 44.0 nmol/L, < 0.001). Tmax values were no different for the two isomers (S-propranolol 130.5 ± 9.8 min; R-propranolol 121.5 ± 10.7 min, N.S.). In all but one patient, the AUC0–4 h was significantly higher for the S-stereoisomer (S-propranolol AUC0–4 h 1217.0 ± 118.5 nmol.h/L, R-propranolol AUC0–4 h 728.8 ± 103.8 nmol.h/L, < 0.0001). Thus, there are marked pharmacokinetic differences between the propranolol stereoisomers that result in about two-fold higher S-propranolol plasma levels after oral drug administration. As demonstrated in Figure 2, there was a linear relationship between total plasma propranolol and the S-propranolol plasma concentrations. There was no difference in the absolute values of S-propranolol concentration or its proportion to total propranolol concentration for any patient with respect to their Child-Pugh classification.

image

Figure 2. .  Relationship between the AUC0–4 h of total plasma propranolol concentrations and its haemodynamically active stereoisomer (S-propranolol) in patients according to their Child-Pugh classification (Child A: ○; Child B: ●; Child C: ◆).

Download figure to PowerPoint

Figure 3 illustrates the plasma concentration vs. time profiles for the two stereoisomers in portal haemodynamic responders and non-responders. None of the pharmacokinetic parameters (AUC0–4 h, Cmax, Tmax), individually calculated for each stereoisomer, or the S/R AUC0–4 h ratio were different for these two haemodynamically defined groups (Table 3). To analyse the impact of propranolol stereoselectivity on the portal haemodynamic response without dividing patients into groups, we calculated the correlations between the pharmacokinetic parameters and the individual haemodynamic response: the mean PBV reduction during the study period did not correlate with either the plasma concentrations of the haemodynamically active isomer (S-propranolol AUC0–4 h, r=– 0.1, Figure 4), the total propranolol plasma concentrations (total propranolol AUC0–4 h, r=– 0.1) or the S/R-propranolol AUC0–4 h ratio (r=– 0.06).

image

Figure 3. .  Average plasma concentration (± s.e.) vs. time profiles of S- and R-propranolol in portal haemodynamic responders (A: upper panel) and non-responders (B: lower panel) after one oral dose of 40 mg propranolol racemate.

Download figure to PowerPoint

Table 3.  . Pharmacokinetic characteristics (mean ± s.e.) of portal haemodynamic responders and non-responders Thumbnail image of
image

Figure 4. .  Correlation between plasma concentrations of the haemodynamically active S-propranolol (AUC0–4 h) and the mean reduction in portal blood velocity (PBV) after one oral dose of 40 mg propranolol racemate.

Download figure to PowerPoint

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

This is the first study to investigate the portal haemodynamic effects of propranolol with respect to the drug’s racemic nature. The potential clinical importance of this issue is illustrated by the fact that R-propranolol, in contrast to S-propranolol, does not affect the smooth musculature and that both isomers exhibit different pharmacokinetics.16, 18

In the present study we found that an oral load with 40 mg propranolol induces a decrease in non-invasively measured PBV which reached a maximum at 2–3 h. Seven of the patients (35%) did not respond adequately (i.e. less than a 20% reduction in PBV). The individual PBV responses were not related to either the S- or R-propranolol plasma levels or to the individual S/R-propranolol ratios.

Propranolol became established in the treatment of portal hypertension more than 15 years ago.24 Its effect on portal haemodynamics is mainly caused by a reduction in cardiac output and splanchnic blood flow. There are numerous clinical and haemodynamic studies which clearly show that propranolol reduces portal hypertension and prevents related upper intestinal bleeding.2[3][4][5][6][7][8][9]–10

In all these studies—even in those that assessed propranolol plasma concentrations10—the fact that propranolol is given as a racemate, with only the S-isomer being haemodynamically active, was not adequately appraised. Following oral administration, propranolol has a high first-pass elimination.25 In healthy subjects this first-pass elimination is more pronounced for the R-isomer, resulting in higher S-propranolol plasma concentrations.18 In this study we could demonstrate that this pharmacokinetic stereoselectivity is preserved in patients with liver cirrhosis, as indicated by the approximately two-fold higher AUC0–4 h for S-propranolol as compared to that for the R-isomer. These results contrast with a study on carvedilol, demonstrating that in patients with liver cirrhosis—when compared to normal subjects—the differences in bioavailability between the two carvedilol enantiomers disappear.19 With respect to propranolol, 2 h after its oral administration, the S-propranolol plasma levels were approximately 30% higher than the R-propranolol concentrations in healthy subjects.18 In contrast, our series of liver cirrhotic patients had S-enantiomer plasma concentrations that on average exceeded the R-propranolol levels by 75% 2 h after oral intake.

The metabolism of both total propranolol14 and its inactive isomer R-propranolol21, 22 has been shown to be severely altered in liver cirrhosis. However, until now no study has assessed the active isomer, S-propranolol, in liver cirrhotics. In our study we found a wide range of plasma S-propranolol concentrations among the patients but a close correlation between these S-propranolol plasma levels and the total propranolol concentrations. This indicates that despite the well-known stereoselectivity of the propranolol metabolism, pharmacokinetic alterations in liver cirrhosis obviously affect both stereoisomers to a similar extent. Thus, total plasma propranolol concentrations, which have commonly been assessed in previous studies,10, 26, 27 can serve as surrogate markers for circulating S-propranolol.

Changes in the propranolol metabolism of liver cirrhotic patients, as described by Arthur et al.,14 are characterized by a prolonged terminal half-life in patients with severely impaired liver function and serum albumin levels below 3 g/dL. In our study population there were 80% Child A and B patients and only 10% had a serum albumin below 3 g/dL. This may explain the lack of any correlation between the severity of liver disease (expressed as Child-Pugh score28) and the S- or R-propranolol AUC0–4 h. The degree of pharmacokinetic stereoselectivity can be expressed as an S/R AUC ratio.29 In our study population, this ratio correlated neither with the severity of the liver disease nor with the portal haemodynamic response.

Among our study population, 35% were propranolol non-responders with respect to the portal haemodynamic effect; a value that agrees well with the literature.9[10]–11 Although numerous studies have addressed the issue of which clinical characteristic predicts the portal haemodynamic response to propranolol, no reliable parameter has so far been identified.6, 9, 10 Similarly, we were not able to identify a clinical parameter (e.g. severity of liver disease, presence of ascites, aetiology of cirrhosis, reduction in heart rate or blood pressure) that allowed us to differentiate between responders and non-responders. Furthermore, none of these parameters correlated with the PBV reduction. As reported by others,12, 30 we observed a trend for more non-responders to have had a previous variceal bleeding (43%) than responders (31%). However, this trend did not reach statistical significance. Furthermore, non-responders had a higher mean arterial blood pressure at baseline.

As reported for total propranolol plasma concentrations,10 our study also showed no correlation between the plasma concentrations of the haemodynamically active S-enantiomer (expressed as AUC0–4 h) and the portal haemodynamic response (PBV reduction). This is conceivable, because there was a linear correlation between S-propranolol and total plasma propranolol concentrations. It might well be that the binding properties of S-propranolol to the receptor or post-receptor mechanisms are the important factors for the haemodynamic effect in liver cirrhosis and not its plasma levels.

In conclusion, we were able to demonstrate that there is a stereoselectivity of propranolol pharmacokinetics in patients with liver cirrhosis and that S-propranolol remains the predominant stereoisomer in plasma. In liver cirrhosis the differences in plasma concentrations between S- and R-propranolol are even more pronounced than previously reported for healthy subjects. Interestingly, among our patients with liver cirrhosis, the S- and R-propranolol clearance was affected to a similar extent. Thus, it is improbable that differences in the splanchnic haemodynamic response to propranolol can be explained by an altered stereoselectivity of the diseased liver.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

The authors thank Ms D. Bammer for her expert technical assistance and PD Dr H. Berthold, Dr T. Sudhop and Dr P. Schiedermaier for their valuable support.

This study was supported by a grant from the University of Bonn, BONFOR grant number 107/08.

This study contains data from the doctoral thesis of Alexander Hoppe.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References
  • 1
    D’Amico G, Pagliaro L, Bosch J. The treatment of portal hypertension: a meta-analytic review. Hepatology 1995; 22: 332 54.
  • 2
    Poynard T, Cales P, Pasta L, et al. Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. N Engl J Med 1991; 324: 1532 8.
  • 3
    Lebrec D, Poynard T, Hillon P, Benhamou JP. Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis. N Engl J Med 1981; 305: 1371 4.
  • 4
    Lebrec D, Hillon P, Munoz C, Goldfarb G, Nouel O, Benhamou JP. The effect of propranolol on portal hypertension in patients with cirrhosis: a hemodynamic study. Hepatology 1982; 2: 523 7.
  • 5
    Hillon P, Lebrec D, Munoz C, Jungers M, Goldfarb G, Benhamou JP. Comparison of the effects of a cardioselective and nonselective beta-blocker on portal hypertension in patients with cirrhosis. Hepatology 1982; 2: 528 31.
  • 6
    Groszmann RJ, Bosch J, Grace ND, et al. Hemodynamic events in a prospective randomized clinical trial of propranolol versus placebo in the prevention of first variceal hemorrhage. Gastroenterology 1990; 99: 1401 7.
  • 7
    Feu F, Garcia-Pagan JC, Bosch J, et al. Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis. Lancet 1995; 346: 1056 9.
  • 8
    Villanueva C, Balanzo J, Novella MT, et al. Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal rebleeding. N Engl J Med 1996; 334: 1624 9.
  • 9
    Bosch J, Mastai R, Kravetz D, et al. Effects of propranolol on azygos blood flow and hepatic and systemic hemodynamics in cirrhosis. Hepatology 1984; 4: 1200 5.
  • 10
    Garcia-Tsao G, Grace ND, Groszmann RJ, et al. Short-term effects of propranolol on portal venous pressure. Hepatology 1986; 6: 101 6.
  • 11
    Vorobioff J, Picabea E, Villavicencio R, et al. Acute and chronic hemodynamic effects of propranolol in unselected cirrhotic patients. Hepatology 1987; 7: 648 53.
  • 12
    Albillos A, Perez-Paramo M, Cacho G, et al. Accuracy of portal and forearm blood flow measurements in the assessment of the portal pressure response to propranolol. J Hepatol 1997; 27: 496 504.
  • 13
    Mills PR, Rae AP, Farah DA, Russell RI, Lorimer AR, Carter DC. Comparison of three adrenoreceptor blocking agents in patients with cirrhosis and portal hypertension. Gut 1984; 25: 73 8.
  • 14
    Arthur MJP, Tanner AR, Patel C, Wright R, Renwick AG, George CF. Pharmacology of propranolol in patients with cirrhosis and portal hypertension. Gut 1989; 26: 14 19.
  • 15
    Stark G, Stark U, Hönigl K, et al. The effects of the propranolol enantiomers on the intracardiac electrophysiological activities of Langendorff-perfused hearts. Basic Res Cardiol; 84: 461 8.
  • 16
    Stoschitzky K, Lindner W, Rath M, et al. Stereoselective hemodynamic effects of (R)- and (S)-propranolol in man. Naunyn-Schmiedeberg’s Arch Pharmacol 1989; 339: 474 8.
  • 17
    Stoschitzky K, Lindner W, Egginger G, et al. Racemic (R,S)-propranolol versus half-dosed optically pure (S)-propranolol in humans at steady state: hemodynamic effects, plasma concentrations and influence on thyroid hormone levels. Clin Pharmacol Ther 1992; 51: 445 53.
  • 18
    Walle T, Webb JG, Bagwell E, Walle U, Daniell HB, Gaffney TE. Stereoselective delivery and actions of beta receptor antagonists. Biochem Pharmacol 1988; 37: 115 24.
  • 19
    Neugebauer G, Gabor M, Reiff K. Disposition of carvedilol enantiomers in patients with liver cirrhosis: Evidence for disappearance of first-pass extraction. J Cardiovasc Pharmacol 1992; 19(Suppl. 1): S142 6.
  • 20
    Stahl E, Baumgartner U, Henke D, Schölmerich J, Mutschler E, Spahn-Langguth H. Rats with portacaval shunt as a potential experimental model for liver cirrhosis: application to carvedilol stereopharmacokinetics. Chirality 1993; 5: 1 7.
  • 21
    Branch RA, James J, Read AE. A study of factors influencing drug disposition in chronic liver disease using the model drug (+)-propranolol. Br J Clin Pharmacol 1976; 3: 243 9.
  • 22
    Pessayre D, Lebrec D, Descatoire V, Peignoux M, Benhamou JP. Mechanism for reduced drug clearance in patients with cirrhosis. Gastroenterology 1978; 74: 566 71.
  • 23
    Spahn-Langguth H, Podkowik B, Stahl E, Martin E, Mutschler E. Improved enantiospecific RP-HPLC assays for Propranolol in plasma and urine with Pronethalol as internal standard. J Anal Toxicol 1991; 15: 327 31.
  • 24
    Lebrec C, Nouel O, Corbic M, Benhamou JP. Propranolol—a medical treatment for portal hypertension? Lancet 1980; 2: 180 2.
  • 25
    Shand DG & Ragno RE. The disposition of Propranolol I. Elimination during oral absorption in man. Pharmacology 1972; 7: 159 68.
  • 26
    Bercoff E, Bataille C, Pariente AE, Valla D, Delhotal B, Lebrec D. Assessment of β-adrenergic blockade with propranolol in patients with cirrhosis . Hepatology 1984; 4: 451 3.
  • 27
    Jiron M, Delhotal B, Lebrec D. Relationship between dose, blood level and haemodynamic response in patients with cirrhosis receiving propranolol. Eur J Clin Pharmacol 1985; 28: 353 5.
  • 28
    Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transsection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60: 646 9.
  • 29
    Piquette-Miller M, Foster RT, Kappagoda CT, Jamali F. Effect of aging on the pharmacokinetics of Acebutolol enantiomers. J Clin Pharmacol 1992; 32: 148 56.
  • 30
    Poynard T, Lebrec D, Hillon P, et al. Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a prospective study of factors associated with rebleeding. Hepatology 1987; 7: 447 51.