ANGIOTENSIN-CONVERTING ENZYME-INHIBITION IN CIRRHOTIC-PATIENTS - PHARMACOKINETICS OF RAMIPRIL

In an open trial, the pharmacokinetics of the angiotensin converting e nzyme inhibitor ramipril and its active metabolite ramiprilat were stu died in 12 patients with liver cirrhosis. After a single oral dose of 5 mg ramipril plasma levels of the parent compound reached peak concen trations of 48.6 +/- 39.8 ng/ml after 0.7 +/- 0.5 h and declined rapid ly to 0.7 +/- 1.2 ng/ml after 8 h. Plasma levels of ramiprilat reached peak concentrations of 3.8 +/- 2.9 ng/ml after 3.0 +/- 2.2 h, thereaf ter declined slowly and could be detected up to 240 h. The total recov ery of ramipril and metabolites in urine within 96 h was on average 46 .0 +/- 10.9% of the administered dose. Major fractions were due to dik etopiperazines and glucuronides of ramipril and ramiprilat. The overal l ACE inhibition was still 92.0 +/- 8.6%. In conclusion, patients with liver cirrhosis had enough capacity to metabolize and excrete the par ent compound ramipril, but had not enough capacity to form ramiprilat, although enough ramiprilat was formed for sufficient ACE inhibition o f about 90%. This indicates that titration of the dose should start wi th 5 mg or even lower doses in patients with markedly impaired liver f unction.