enalapril and Liver-Diseases

The aim of our study was to analyze drug-induced liver disease over a 3-year period in one gastroenterological department.. International consensus standard definitions and criteria for assessing causality of adverse drug reactions were applied to all patients with abnormal hepatic test results.. Drugs were implicated in hepatic injury in 14 patients (8 females) in whom causal relationship between drug and liver disease was definite or highly probable. The drugs responsible were amoxicillin with clavulanic acid (3 cases), fluvastatin and pravastatin (3 cases), antituberculous drugs (2 cases), estrogens, roxithromycin, asacol, satolol, enalapril and thiamazol. A total of 78.6% (11 cases) were classified as hepatocellular or mixed hepatitis, while cholestatic injury was found in 21.4% (3 cases). There were no lethal or severe (prothrombin < 50%) hepatic drug reactions. In 13 patients the course of liver disease after withdrawal of the offensive drug was either acute or protracted, while in one patient there was chronic cholestasis (>3 years) resulting from injury to interlobular bile ducts by amoxicllin with clavulanic acid.. A thorough history of drug intake should be taken in all patients presenting with abnormal hepatic test results. Amoxicillin & clavulanic acid, cholesterol-lowering and antituberculin drugs were the most frequent hepatotoxic factors in our patients. In a majority of cases the liver injury was not severe, and resolved after prompt withdrawal of the responsible drug.

Topics: Adult; Aged; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Anticholesteremic Agents; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Comorbidity; Enalapril; Estrogens; Fatty Liver; Female; Humans; Liver Diseases; Male; Mesalamine; Middle Aged

Increasing evidence suggests that altered methionine/folate metabolism may contribute to the development of hepatic injury. We addressed the question of whether folic acid (FA) supplementation can affect serum alanine aminotransferase (ALT) level in hypertensive Chinese adults.. A total of 480 participants with mild or moderate essential hypertension and without known hepatic disease were randomly assigned to three treatment groups: (1) enalapril only (10 mg, control group); (2) enalapril-FA tablet (10 mg enalapril combined with 0.4 mg of FA, low FA group); and (3) enalapril-FA tablet (10 mg enalapril combined with 0.8 mg of FA, high FA group), once daily for 8 weeks.. This report included 455 participants in the final analysis according to the principle of intention to treat. We found a significant reduction in ALT level in the high FA group (median (25th percentile, 75th percentile), -0.6 (-6.9, 2.0)IU/l, P=0.0008). Compared with the control group, the high FA group showed a significantly greater ALT-lowering response in men (median ALT ratio (ALT at week 8 to ALT at baseline; 25th percentile, 75th percentile): 0.93 (0.67, 1.06) vs 1.00 (0.91, 1.21), P=0.032), and in participants with elevated ALT (ALT>40 IU/l) at baseline. There was no difference in ALT lowering between the control and the low FA group.. Compared with treatment using 10 mg of enalapril alone, a daily dose of 10 mg enalapril combined with 0.8 mg of FA showed a beneficial effect on serum ALT level, particularly in men and in participants with elevated (>40 IU/l) ALT.

Topics: Aged; Alanine Transaminase; Antihypertensive Agents; Dietary Supplements; Double-Blind Method; Enalapril; Female; Folic Acid; Humans; Hypertension; Liver Diseases; Male; Middle Aged; Sex Factors; Vitamin B Complex

The pharmacokinetics and haemodynamic effects of orally administered spirapril, a novel angiotensin-converting enzyme (ACE) inhibitor, have been investigated in patients with liver cirrhosis (n = 10), in patients with chronic, non-cirrhotic liver disease (n = 8) and in a control group of healthy subjects (n = 16). The absorption and elimination of spirapril did not differ between patients with liver disease and control subjects. In contrast, the bioavailability of spiraprilat, the metabolite responsible for the pharmacological action of spirapril, was significantly reduced in patients (AUC 820 micrograms.h.l-1, 923 micrograms.h.l-1 and 1300 micrograms.h.l-1 in patients with cirrhosis, patients with non-cirrhotic liver disease and in healthy subjects, respectively. Compared to healthy subjects, cirrhotic patients had a reduced rate constant of spiraprilat formation (1.10 h-1 in patients vs. 2.00 h-1 in control subjects) while the elimination half-life of spiraprilat was not different. The effect of spirapril on diastolic blood pressure was decreased in patients with chronic liver disease as compared to the controls. Thus, the pharmacokinetics of spirapril was unchanged in patients with different types of liver disease, including cirrhosis. However, the bioavailability of spiraprilat and hypotensive effect of spirapril were reduced in patients.

Topics: Administration, Oral; Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Chronic Disease; Enalapril; Female; Glycogen Storage Disease; Half-Life; Hemodynamics; Humans; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Diseases; Male; Middle Aged; Pulse

Spirapril is a prodrug that is converted by esterolysis to the active (but poorly absorbed) diacid spiraprilat. After intravenous infusion, the disposition of spirapril is monophasic with a terminal half-life of 20-50 minutes. Plasma clearance was 56 l/h and renal clearance was 11 l/h; the volume of distribution was 28 litres. After intravenous infusion of spiraprilat, the disposition was biphasic with half-lives of 2 hours and 35 hours, respectively. Plasma clearance of spiraprilat was 10 l/h, of which 7.6 l/h was cleared by the kidneys. The volume of distribution was 43 litres. The bioavailability of orally administered spirapril was 50% whereas the bioavailability of orally administered spiraprilat was virtually zero. There was a significant first-pass metabolism of spirapril after oral administration. The pharmacokinetics of spirapril were linear within the dose range of 6-50 mg whereas the disposition of spiraprilat was non-linear with respect to the terminal phase. Variability of the pharmacokinetic parameters of spiraprilat were significantly less than that of spirapril. Plasma concentrations of both spirapril and spiraprilat were increased by 30% in the elderly. Similarly, in patients with impaired liver function, plasma concentrations of spiraprilat were reduced by 30%. In patients with severe renal impairment, spiraprilat concentrations were significantly increased by a factor of 3-4. Spirapril showed no clinically relevant drug interactions with either glibenclamide, diclophenac, cimetidine, rifampicin, hydrochlorothiazide or nicardipine.

Topics: Adult; Age Factors; Aged; Angiotensin-Converting Enzyme Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Enalapril; Humans; Kidney Diseases; Liver Diseases; Reference Values

The effects of modulators of cytochrome P450 and reduced glutathione (GSH) on the hepatotoxicity of enalapril maleate (EN) were investigated in Fischer 344 rats. Twenty-four hours following the administration of EN (1.5 to 1.8 g/kg), increased serum transaminases (ALT and AST) and hepatic necrosis were observed. Pretreatment of the animals with pregnenolone-16 alpha-carbonitrile, a selective inducer of the cytochrome P450IIIA gene subfamily, enhanced EN-induced hepatotoxicity, whereas pretreatment with the cytochrome P450 inhibitor, cobalt protoporphyrin, reduced the liver injury. Depletion of hepatic non-protein sulfhydryls (NPSHs), an indicator of GSH, by combined treatment with buthionine sulfoximine (BSO) and diethyl maleate (DEM) produced marked elevations in serum transaminases by 6 hr after EN treatment. Administered on its own, EN decreased hepatic NPSH content and when combined with the BSO/DEM pretreatment, the liver was nearly completely devoid of NPSHs. Protection from EN-induced hepatotoxicity was observed in animals administered L-2-oxothiazolidine-4-carboxylic acid, a cysteine precursor. Together, these observations suggest the involvement of cytochrome P450 in EN bioactivation and GSH in detoxification. The results corroborate previous in vitro observations pertaining to the mechanism of EN-induced cytotoxicity towards primary cultures of rat hepatocytes. Although the doses of EN used in this study were far in excess of therapeutic doses, under certain circumstances, this metabolism-mediated toxicologic mechanism could form the basis for idiosyncratic liver injury in patients receiving EN therapy.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Biomarkers; Biotransformation; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Enalapril; Enzyme Induction; Glutathione; Inactivation, Metabolic; Liver; Liver Diseases; Male; Necrosis; Pregnenolone Carbonitrile; Protoporphyrins; Pyrrolidonecarboxylic Acid; Rats; Rats, Inbred F344; Sulfhydryl Compounds; Thiazoles; Thiazolidines

To present evidence that enalapril and captopril may produce hepatotoxicity by a common mechanism.. A case report and review of pertinent literature.. A patient developed hepatotoxicity once while taking enalapril and again while taking captopril. Hepatotoxicity resolved with cessation of therapy. Hepatotoxicity has been reported with use of captopril, enalapril, and lisinopril. Apparent cross-reactivity has been reported on just one other occasion.. Because hepatotoxicity is uncommon with angiotensin-converting enzyme (ACE) inhibitors, our observations suggest the possibility that these agents produce hepatotoxicity by a common mechanism. In patients who develop hepatotoxicity while taking one ACE inhibitor, other agents in this class probably should be avoided.

Topics: Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Captopril; Chemical and Drug Induced Liver Injury; Enalapril; Humans; Liver Diseases; Male; Middle Aged

The aim of the study was to define a therapy to be combined with an immunosuppressive drug such as cyclosporin A, in order to partially reduce the nephrotoxic and hepatotoxic effects in the treated rats. Two drugs were considered: enalapril, which is an inhibitor of the angiotensin-converting enzyme, and spironolactone, which is an antagonist of aldosterone. These two drugs interrupt the renin-angiotensinogen-angiotensin chain after this has been activated by cyclosporin A, preventing peripheral vasoconstriction and more specifically the constriction of both glomerular arterioles and hepatic vessels from occurring, thus diminishing the cyclosporin A toxicity in both liver and kidney.

Topics: Animals; Chemical and Drug Induced Liver Injury; Cyclosporine; Drug Therapy, Combination; Enalapril; Kidney Diseases; Liver Diseases; Male; Rats; Rats, Sprague-Dawley; Spironolactone

The in vitro conversion of enalapril (MK421) to enalaprilic acid (MK422) in human autopsy tissues was examined. MK422 was measured by radioimmunoassay. Human cadaver liver was the only tissue in which significant conversion was demonstrated. The esterase activity was stable after post mortem. Autopsy liver tissues from patients with elevated ante mortem liver function tests were found to have a reduced rate of deesterification.

Topics: Angiotensin-Converting Enzyme Inhibitors; Biotransformation; Dipeptides; Enalapril; Enalaprilat; Esterases; Humans; In Vitro Techniques; Liver; Liver Diseases; Liver Function Tests; Proteins; Radioimmunoassay