PHARMACOKINETICS AND HEMODYNAMIC-EFFECTS OF A SINGLE ORAL DOSE OF THENOVEL ACE-INHIBITOR SPIRAPRIL IN PATIENTS WITH CHRONIC LIVER-DISEASE

The pharmacokinetics and haemodynamic effects of orally administered s pirapril, a novel angiotensin-converting enzyme (ACE) inhibitor, have been investigated in patients with liver cirrhosis (n = 10), in patien ts 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 contr ol subjects. In contrast, the bioavailability of spiraprilat, the meta bolite responsible for the pharmacological action of spirapril, was si gnificantly reduced in patients (AUC 820 mug . h . l-1, 923 mug . h . l-1 and 1300 mug . h . l-1 in patients with cirrhosis, patients with n on-cirrhotic liver disease and in healthy subjects, respectively. Comp ared to healthy subjects, cirrhotic patients had a reduced rate consta nt of spiraprilat formation (1.10 h-1 in patients vs. 2.00 h-1 in cont rol subjects) while the elimination half-life of spiraprilat was not d ifferent. The effect of spirapril on diastolic blood pressure was decr eased in patients with chronic liver disease as compared to the contro ls. Thus, the pharmacokinetics of spirapril was unchanged in patients with different types of liver disease, including cirrhosis. However, t he bioavailability of spiraprilat and hypotensive effect of spirapril were reduced in patients.