spirapril and Liver-Diseases

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