Angiotensin-converting enzyme (ACE)-inhibition in cirrhosis. Pharmacokinetics and dynamics of the ACE-inhibitor cilazapril (Ro 31-2848).
The angiotensin-converting enzyme (ACE)-inhibitor, cilazapril, is converted to its active metabolite, cilazaprilat, by ester hydrolysis in the liver. The pharmacokinetics and pharmacodynamics of a single 1 mg oral dose of cilazapril were investigated in 10 healthy volunteers and in 9 cirrhotic patients with compensated cirrhosis and portal hypertension. A significantly increased mean plasma peak concentration (40.0 +/- 13.6 ng/ml vs. 25.5 +/- 7.9 ng/ml; p < 0.05) and a decreased apparent oral clearance (7.8 +/- 6.0 l/h vs. 16.4 +/- 5.4 l/h; p < 0.05) of cilazapril were found in cirrhotic patients compared to healthy volunteers. The plasma concentration of cilazaprilat declined in 2 phases. In both phases the plasma half-life was significantly longer in patients with cirrhosis (1st phase: 2.5 +/- 0.8 h vs. 1.7 +/- 0.6 h; p < 0.05; 2nd phase: 46.2 +/- 16.6 h vs. 28.8 +/- 4.7 h; p < 0.001). Consequently, cilazaprilat concentrations at 24 h were higher in patients than in volunteers (1.42 +/- 0.33 ng/ml vs. 0.87 +/- 0.14 ng/ml; p < 0.001). The predose activity of the ACE (26.3 +/- 7.3 U/l vs. 16.8 +/- 4.5 U/l; p < 0.005) and plasma renin activity (3.3 +/- 3.2 ng/ml/h vs. 1.4 +/- 1.0 ng/ml/h) were higher in patients than in volunteers. Maximum ACE-inhibition occurred at similar times in patients (2.7 h) and volunteers (2.3 h). Maximum ACE-inhibition was slightly higher in volunteers (94.6%) than in patients (90.6%). At later time points (> 24 h), however, ACE-inhibition was more pronounced in patients (at 72 h: 39.6 +/- 6.9% vs. 23.5 +/- 8.2%; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Gross
V
V
Department of Internal Medicine, University of Freiburg, Germany.
Treher
E
E
Haag
K
K
Neis
W
W
Wiegand
U
U
Schölmerich
J
J
D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects*; D002802:Cholinesterases / Q000097:blood; D017315:Cilazapril / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003404:Creatinine / Q000378:metabolism; D005260:Female; D005690:Galactose / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood / Q000378:metabolism / Q000503:physiopathology*; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D012083:Renin / Q000097:blood; D012709:Serum Albumin / Q000032:analysis
D000806:Angiotensin-Converting Enzyme Inhibitors; D012709:Serum Albumin; D017315:Cilazapril; D003404:Creatinine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D002802:Cholinesterases; D012083:Renin; D001663:Bilirubin; C045980:cilazaprilat; D005690:Galactose