Pharmacokinetics and haemodynamic effects of a single oral dose of the novel ACE inhibitor spirapril in patients with chronic liver disease

Krähenbühl, Stephan; Grass, Peter; Surve, A. H.; Kutz, K; Reichen, Jürg

doi:10.1007/bf00315391

Cited by 10 publications

(16 citation statements)

References 26 publications

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“…Similar correlations have also been described in previous studies of drug-disposition in patients with cirrhosis [41]. Since they could not be described by a linear mathematical function (as was the case for SBA concentration), however, they cannot be used to extrapolate dosing recommendations for propranolol in patients with liver cirrhosis.…”

Section: Discussionsupporting

confidence: 70%

A Study of the Relationship between Serum Bile Acids and Propranolol Pharmacokinetics and Pharmacodynamics in Patients with Liver Cirrhosis and in Healthy Controls

et al. 2014

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The main objectives of the study were to determine the exposure and bioavailability of oral propranolol and to investigate their associations with serum bile acid concentration in patients with liver cirrhosis and in healthy controls. A further objective was to study the pharmacodynamics of propranolol. An open-label crossover study was performed to determine the pharmacokinetics and pharmacodynamics of propranolol after oral (40 mg) and intravenous (1 mg) administration as well as the concentration of total and individual fasting serum bile acids in 15 patients with liver cirrhosis and 5 healthy controls. After intravenous propranolol, patients showed a 1.8-fold increase in the area under the plasma concentration-time curve (AUC0–∞), a 1.8-fold increase in volume of distribution and a 3-fold increase in the elimination half-life (mean ± SEM: 641±100 vs. 205±43 minutes) compared to controls. After oral application, AUC0–∞ and elimination half-life of propranolol were increased 6- and 4-fold, respectively, and bioavailability 3-fold (83±8 vs. 27±9.2%). Maximal effects on blood pressure and heart rate occurred during the first 4 and first 2 hours, respectively, after intravenous and oral application in both patients and controls. Total serum bile acid concentrations were higher in patients than controls (42±11 vs. 2.7±0.3 µmol/L) and were linearly correlated with the serum chenodeoxycholic acid concentration. There was a linear correlation between the SBA concentration and propranolol oral AUC0–∞ in subjects not receiving interacting drugs (r2 = 0.73, n = 18). The bioavailability of and exposure to oral propranolol are increased in patients with cirrhosis. Fasting serum bile acid concentration may be helpful in predicting the exposure to oral propranolol in these patients.

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Section: Discussionsupporting

confidence: 70%

A Study of the Relationship between Serum Bile Acids and Propranolol Pharmacokinetics and Pharmacodynamics in Patients with Liver Cirrhosis and in Healthy Controls

et al. 2014

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“…[78] Studies of enalapril and spirapril showed a prolonged elimination half-life for the diacid, consistent with a reduction in clearance. [68,77] This would suggest that, with these drugs, inhibition of the conversion of prodrug to diacid may be compensated by reduced clearance of the diacid metabolite formed. Equally, without an alternative elimination pathway, it may be that only the rate and not the extent of formation of the diacid is reduced, and that its elimination is unchanged.…”

Section: Prodrug Metabolismmentioning

confidence: 97%

“…The authors concluded that the measured serum creatinine level was inaccurate in predicting GFR in cirrhosis because of reduced muscle mass and reduced conversion of creatine to creatinine resulting from hepatic impairment. The calculated creatinine clearance, which uses the serum creatinine level, was also inaccurate in predicting GFR 600 (68) 381 because of use in the nomogram of body weight that was likely to be inflated due to the presence of ascites. The measured creatinine clearance was inaccurate because of an increased fractional tubular secretion of creatinine as the GFR deteriorated.l'<'…”

Section: Creatinine Clearance As a Marker Of Renal Function In Liver mentioning

confidence: 98%

“…[68][69][70][71] Where the biliary elimination of unchanged drug was impaired, there was a concomitant increase in urinary excretion of unchanged drug.l [69][70][71] Another study concluded that the biliary elimination of the diacid metabolite of temocapril was not altered in cirrhosis; [72] however, impaired formation of the diacid metabolite may have obscured a reduction in its biliary elimination. In patients with advanced cirrhosis, the clearance of rocuronium was found to be the same as in healthy individuals.…”

Section: Biliary Excretionmentioning

confidence: 99%

“…Conversion of enalapril, [76.77] cilazapril.F'l perindopril.Uf spirapril, [68] and possibly temocapril [72] to their respective diacid metabolites is substantially reduced in cirrhosis, reflecting impaired ester hydrolysis. However, with the exception of cilazapril.P'" this seems to be of no clinical significance because ACE inhibition and the antihypertensive effect of these drugs are not altered in cirrhosis.l68.…”

Section: Prodrug Metabolismmentioning

confidence: 99%

See 2 more Smart Citations

Clinical Pharmacokinetic and Pharmacodynamic Considerations in Patients with Liver Disease

Morgan

McLean

1995

Clinical Pharmacokinetics

193

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The effects of liver disease on pharmacokinetics and pharmacodynamics are highly variable, and difficult to predict as the mechanisms of these effects are not well understood. Since the majority of the published literature is concerned with cirrhotic liver disease, this review also focuses mainly on this area. Four different theories have been proposed to account for the effects of chronic liver disease with cirrhosis on hepatic drug elimination: the sick cell theory; the intact hepatocyte theory; the impaired drug uptake theory; and the oxygen limitation theory. While some data in support of each of the first 2 theories have been published recently, a large amount of clinical data would appear to refute both of these theories. These clinical data are substantially consistent with the latter 2 theories, which regard the decreased permeability of the capillarised sinusoid as the critical feature in cirrhosis. Further work is required to determine the applicability of each of these theories. In cirrhosis, drug glucuronidation is spared relative to oxidative drug metabolism; however, in advanced cirrhosis this pathway may also be impaired substantially. There is evidence that in cirrhosis other conjugation pathways may also be impaired to variable degrees. Growing evidence suggests that biliary drug excretion is impaired in cirrhosis. Recent studies with several racemic drugs indicate that the disease can have different effects on the hepatic elimination of individual enantiomers, which may lead to a change in the concentration-response relationships of racemic drugs in cirrhosis. A major finding which has emerged in recent years is that, even with moderate degrees of hepatic impairment, there is a decrease in clearance of drugs or active metabolites normally cleared by the kidney. The effect on renal clearance of unbound drug may be masked if there is a concomitant decrease in plasma protein binding of the drug. Neither serum creatinine levels nor creatinine clearance are useful markers of the renal dysfunction associated with cirrhosis. Both may greatly overestimate renal function in patients with cirrhosis due to increased fractional renal tubular secretion of creatinine. Altered receptor sensitivity has been observed with some drugs in cirrhosis, while for other drugs there is no change in pharmacodynamics. Precise determination of drug dosage in cirrhosis requires information on changes in pharmacodynamics and plasma protein binding in addition to changes in drug elimination. Pharmacokinetic investigations in a variety of chronic liver diseases without cirrhosis (e.g. carcinoma, schistosomiasis and viral hepatitis) suggest that in the absence of cirrhosis, impairment of drug elimination is not sufficient to warrant reduction of drug dosage. However, if cirrhosis is present, 'safe' drug use requires an awareness of the possibility of multiple interactions between changes in hepatic and renal disposition and pharmacodynamics. In chronic liver disease with cirrhosis, dosage reduction is the general rule regardless...

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Prescribing in liver disease

Reichen

1997

Journal of Hepatology

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Pharmacokinetics and haemodynamic effects of a single oral dose of the novel ACE inhibitor spirapril in patients with chronic liver disease

Cited by 10 publications

References 26 publications

A Study of the Relationship between Serum Bile Acids and Propranolol Pharmacokinetics and Pharmacodynamics in Patients with Liver Cirrhosis and in Healthy Controls

A Study of the Relationship between Serum Bile Acids and Propranolol Pharmacokinetics and Pharmacodynamics in Patients with Liver Cirrhosis and in Healthy Controls

Clinical Pharmacokinetic and Pharmacodynamic Considerations in Patients with Liver Disease

Prescribing in liver disease

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