Angiotensin-converting enzyme inhibition in cirrhotic patients--pharmacokinetics of ramipril

In an open trial, the pharmacokinetics of the angiotensin converting enzyme inhibitor ramipril and its active metabolite ramiprilat were studied in 12 patients with liver cirrhosis. After a single oral dose of 5 mg ramipril plasma levels of the parent compound reached peak concentrations of 48.6 +/- 39.8 ng/ml after 0.7 +/- 0.5 h and declined rapidly 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, thereafter declined slowly and could be detected up to 240 h. The total recovery 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 diketopiperazines and glucuronides of ramipril and ramiprilat. The overall ACE inhibition was still 92.0 +/- 8.6%. In conclusion, patients with liver cirrhosis had enough capacity to metabolize and excrete the parent compound ramipril, but had not enough capacity to form ramiprilat, although enough ramiprilat was formed for sufficient ACE inhibition of about 90%. This indicates that titration of the dose should start with 5 mg or even lower doses in patients with markedly impaired liver function.