The pharmacokinetics of enalapril in patients with compensated liver cirrhosis.

Baba, Tsuyoshi; Murabayashi, S; Tomiyama, T.; Takebe, Kazuo

doi:10.1111/j.1365-2125.1990.tb03700.x

Cited by 18 publications

(11 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[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: 96%

Clinical Pharmacokinetic and Pharmacodynamic Considerations in Patients with Liver Disease

Morgan

McLean

1995

Clinical Pharmacokinetics

193

View full text Add to dashboard Cite

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...

show abstract

Section: Prodrug Metabolismmentioning

confidence: 96%

Clinical Pharmacokinetic and Pharmacodynamic Considerations in Patients with Liver Disease

Morgan

McLean

1995

Clinical Pharmacokinetics

193

View full text Add to dashboard Cite

show abstract

“…ble port-caval shunting, as is suggested in human patients with compensated liver cirrhosis [1]. Normal or higher plasma benazeprilat concentrations suggest that the biotransformation ability from benazepril to benazeprilat is normal or even higher in dogs with ascitic heartworm disease in spite of liver injury.…”

Section: Discussionmentioning

confidence: 90%

An Angiotensin Converting Enzyme Inhibitor, Benazepril Can Be Transformed to an Active Metabolite, Benazeprilat, by the Liver of Dogs with Ascitic Pulmonary Heartworm Disease

Kitagawa

Ohba

Kuwahara

et al. 2003

The Journal of Veterinary Medical Science

View full text Add to dashboard Cite

ABSTRACT. To examine whether an angiotensin converting enzyme (ACE) inhibitor, benazepril, can be transformed to the active metabolite, benazeprilat, by severely injured liver of dogs with ascitic heartworm disease, benazepril hydrochloride was administered orally to dogs once daily for 7 consecutive days at a dose rate of 0.29 mg/kg to 0.63 mg/kg of body weight, and plasma benazepril and benazeprilat concentrations were determined on the 1st and 7th administration days. In 7 dogs with ascitic pulmonary heartworm disease, plasma benazeprilat concentrations tended to be higher than in 7 control dogs both on the 1st and 7th administration days. The peak concentration and area under the concentration-time curve tended to be greater in dogs of the ascites group than in control dogs, but the statistics could not detect significant differences in the time to peak concentration and t 1/2 between the control and ascites groups. Plasma ACE activities decreased after administration of benazepril. In dogs with ascitic heartworm disease, benazepril was readily transformed to benazeprilat by the liver, and was effective for suppression of plasma ACE activity.

show abstract

“…A recent study suggested that severe hepatic insufficiency was associated with a decrease in the deesterification of enalapril, another prodrug ACE inhibitor, to its active metabolite enalaprilat (Ohnishi et al, 1989). However, moderate hepatic impairment may have little effect on the disposition kinetics of enalapril (Baba et al, 1990) and perindopril (Tsai et al, 1989). We, therefore, examined the disposition kinetics of perindopril and its metabolites in patients with liver cirrhosis.…”

Section: Introduction Methodsmentioning

confidence: 99%

The pharmacokinetics of perindopril in patients with liver cirrhosis.

Thiollet

Funck‐Brentano

Grange

et al. 1992

Brit J Clinical Pharma

View full text Add to dashboard Cite

Perindopril is a non‐sulphydryl angiotensin converting enzyme (ACE) inhibitor which requires hydrolysis to its active metabolite, perindoprilat, to produce its effects. Ten cirrhotic patients with mild to severe disease were studied after oral administration of a single 8 mg dose of perindopril as its tert‐butylamine salt. Compared with a historical control group of young healthy volunteers receiving the same single oral dose of perindopril, mean AUC values of the prodrug perindopril were double in patients with liver cirrhosis (602 +/‐ 294 s.d. ng ml‐1 h vs 266 +/‐ 70 s.d. ng ml‐1 h) whereas the mean AUC of perindoprilat was found to be similar (134 +/‐ 139 ng ml‐1 h vs 120 +/‐ 29 ng ml‐1 h). The partial metabolic clearance of perindopril to perindoprilat was much lower in the cirrhotics (26 +/‐ 12 ml min‐1 vs 58 +/‐ 22 ml min‐1). The maximum inhibition of plasma ACE activity measured in the cirrhotic patients (87.5 +/‐ 5.1%) was comparable with that previously reported with perindopril in patients with mild hepatic impairment as well as in patients with essential hypertension. We suggest that liver cirrhosis may be associated with imparied deesterification of perindopril to its active metabolite perindoprilat but that no dosage adjustment of perindopril is required in cirrhotic patients.

show abstract

The pharmacokinetics of enalapril in patients with compensated liver cirrhosis.

Cited by 18 publications

References 7 publications

Clinical Pharmacokinetic and Pharmacodynamic Considerations in Patients with Liver Disease

Clinical Pharmacokinetic and Pharmacodynamic Considerations in Patients with Liver Disease

An Angiotensin Converting Enzyme Inhibitor, Benazepril Can Be Transformed to an Active Metabolite, Benazeprilat, by the Liver of Dogs with Ascitic Pulmonary Heartworm Disease

The pharmacokinetics of perindopril in patients with liver cirrhosis.

Contact Info

Product

Resources

About