The pharmacokinetics and bioavailability of cilazapril in normal man.

Abstract

1 The pharmacokinetics of cilazapril and its active metabolite, cilazaprilat, were investigated in a three-part crossover study in 12 healthy male volunteers aged 19-38 years, excluding one subject who withdrew from the study. 2 Single 2.5 mg oral doses of cilazapril, and equivalent oral and intravenous doses of cilazaprilat were administered as aqueous solutions to the fasted subjects. There was an interval of 1 week between treatments. Concentrations of cilazapril and cilazaprilat in plasma and urine, and activities of angiotensin converting enzyme (ACE) in plasma were measured by radioenzymatic methods.3 After 10 min infusion of cilazaprilat, the mean plasma concentration was 194 ng ml-', and ACE inhibition was almost 100%. The decline in concentrations was polyphasic, with mean half-lives for the periods 1-4 h and 24-168 h of 0.90 h and 46 h, respectively. Between 4 and 24 h the decline was non-linear, and ACE inhibition decreased from 91% to 67%. Urinary recovery of cilazaprilat averaged 91% of dose. 4 After oral cilazapril, the parent drug was rapidly absorbed and rapidly eliminated, with a mean maximum plasma concentration of 82 ng ml-' at 0.83 h and a single elimination half-life of 1.3 h. Cilazaprilat peaked at 36 ng ml-' about 1.7 h after dosing and the decline in concentrations was biphasic, with half-lives of 1.8 h and 45 h. After oral cilazaprilat, plasma concentrations were considerably lower, and the peak later (2.2 h). 5 Urinary recovery data indicated an absolute bioavailability for cilazaprilat of 57% (range 45-75%) from oral cilazapril, but only 19% (range 8-40%) from oral cilazaprilat.6 The plasma data for cilazaprilat suggest that the first phase of the kinetics after oral cilazapril is controlled by the rate of hydrolysis of the parent drug, whereas the terminal phase is controlled by tight binding to ACE. Clearance of cilazaprilat is almost exclusively renal.

Pharmacokinetics and haemodynamic effects of the angiotensin converting enzyme inhibitor cilazapril in hypertensive patients with normal and impaired renal function

“…Longer times to peak after lower dosages of cilazapril have also been reported in normal volun teers [2], In addition, the slower excretion of cilazaprilat in the low clearance groups may have contributed to the longer times to peak. Theoretically, slower intestinal In our patients with normal as well as in those with absorption of cilazapril in the low clearance groups may impaired renal function the pharmacokinetic data of the also explain this difference, but studies with other ACE Discussion single dose part were comparable with the results inhibitors are not in favour of such obtained by others [1,3,4]. A strong relationship…”

“…and ACE activity were performed by radioenzymatic Patients were divided in four groups: creatinine clearance methods [1]. During chronic treatment these were (CLcr)> 100 ml m in" 1 (group A), CLcr 41-100 ml min" 1 (group C) and CL (group B), CLcr 21-40 ml min 1 measured at all visits at 24 h after drug administration r and additionally at week 2 and 4 at 3 h after drug 8-20 ml min ~1 (group D).…”

“…This metabolite is excreted mainly by the kidneys [1]. In patients with normal renal function most of the unbound cilazaprilat is rapidly excreted in the first 8 h after drug administration.…”

“…In patients with normal renal function most of the unbound cilazaprilat is rapidly excreted in the first 8 h after drug administration. However, probably due to the high affinity of cilazaprilat for angiotensin converting enzyme the terminal half-life of this drug is as long as 40 to 50 h [1,2]. In patients with renal insufficiency only limited pharmacokinetic and pharmacodynamic data on chronic cilazaprilat administration are available [3][4][5].…”

A pharmacokinetic study of cilazapril in patients with congestive heart failure.

“…In the patients, the maximum concentration was higher (6.8 ng ml-l vs 5.4 ng ml-1), the time of maximum somewhat later (2.3 h vs 1.8 h) and the AUC(24) greater (59 ng ml-1 h vs 42 ng ml-' h). Both CHF and age (Williams et al, 1989b) may have had some effect on the pharmacokinetics of cilazaprilat. In addition, cilazaprilat clearance is known to be non-linear at low plasma concentrations because of binding to plasma ACE (Williams et al, 1989a).…”