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-1, 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-1 at 0.83 h and a single elimination half-life of 1.3 h. Cilazaprilat peaked at 36 ng ml-1 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.
Keywords: cilazapril, cilazaprilat, pharmacokinetics, absolute bioavailability
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