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)

Antihypertensive treatment with cilazapril. Resting and exercise blood pressure, hormones and enzymes.

The effects of the angiotensin-converting enzyme (ACE) inhibitor cilazapril (Ro 31-2848) on resting and exercise blood pressure (BP) as well as on hormonal and enzyme activities were evaluated following a more than one year long-term treatment. After an initial placebo wash-out (mean sitting BP 151/101), n = 13 hypertensive patients were on cilazapril treatment (1.25, 2.5 or 5 mg/d; in 2 cases with 25 mg hydrochlorothiazide additionally) for 78 (70 to 82) weeks (phase A, mean sitting BP 137/91). Thereafter, they underwent a second placebo wash-out of 4.4 (1 to 10) weeks (phase B, mean sitting BP 137/94) again followed by cilazapril treatment of 9.5 (4 to 14) weeks (phase C, mean sitting BP 137/91) to titrate the minimum antihypertensive dose. At the end of each phase, blood pressure was measured at rest and during isotonic (bicycle) and isometric (handgrip) exercise, and hormones and enzymes were evaluated 4 h post-dose.