Pharmacokinetics of intravenous cilazaprilat in normal volunteers.

Whitehead, E. M.; Walters, G. E.; Williams, Paul; Johnston, G. D.

doi:10.1111/j.1365-2125.1989.tb03453.x

Cited by 10 publications

(5 citation statements)

References 6 publications

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“…The higher peak concentrations in the elderly volunteers could have been related to a combination of faster absorption/hydrolysis and slower clearance from plasma. The lower plasma clearance in the elderly was consistent with the reduced renal clearance since renal excretion is almost the only elimination route of cilazaprilat (Whitehead et al, 1988). In turn, the reduced renal clearance correlated with decreased renal function as shown by lower creatinine clearance.…”

Section: Discussionsupporting

confidence: 53%

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A pharmacokinetic study of cilazapril in elderly and young volunteers.

Williams¹,

Brown²,

Rajaguru³

et al. 1989

Brit J Clinical Pharma

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1 Cilazaprilat is an inhibitor of angiotensin converting enzyme (ACE) and is the active metabolite of cilazapril. The pharmacokinetics of cilazaprilat, and the inhibition of plasma ACE were investigated in 12 elderly and 12 young healthy volunteers. 2 Single oral 1 mg doses of cilazapril were given to the elderly (age range 65-83 years) and the young (age range 18-31 years) in an open study. Plasma and urinary cilazaprilat concentrations, and plasma ACE activities were measured up to 72 h after dosing by radioenzymatic methods. 3 Cilazapril was well tolerated in both young and elderly subjects. Small falls in blood pressure were observed up to 8-24 h after dosing.4 The mean peak plasma cilazaprilat concentration in the elderly (11.5 ng ml-') was significantly greater (P < 0.02) than the corresponding value in the young (8.3 ng ml-').Total and renal clearances were significantly lower (both P < 0.05) in the elderly (12.8 and 5.1 1 h-1) than in the young (16.0 and 7.21 h-1). Total urinary recovery of cilazaprilat was similar for the two groups at about 43% of dose. 5 Plasma ACE inhibition was slightly greater in the elderly but the mean inhibition in the two groups did not differ by more than 10% at any time-point from 1-72 h. 6 The plasma concentrations of cilazaprilat required for 90% ACE inhibition were similar at 4.7 and 4.8 ng ml-1 in the elderly and young respectively. 7 It is concluded that the age-related changes in cilazaprilat kinetics and in the degree of ACE inhibition are small. On their own, these changes do not imply a need for reduced dosage in the elderly but further clinical experience will help to establish a suitable dosage regimen of cilazapril for elderly hypertensives.

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Section: Discussionsupporting

confidence: 53%

“…Cilazapril is being evaluated for the treatment cilazaprilat (Whitehead et al, 1988). As renal of essential hypertension and congestive heart function tends to decline with age (Greenblatt failure.…”

Section: Introductionmentioning

confidence: 99%

A pharmacokinetic study of cilazapril in elderly and young volunteers.

Williams¹,

Brown²,

Rajaguru³

et al. 1989

Brit J Clinical Pharma

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“…Cilazapril is rapidly enzyme (ACE) (Natoff et al, 1985). There is a hydrolysed by non-specific esterases to the close relationship between the pharmacokinetics of cilazaprilat and the dynamics of plasma ACE inhibition (Francis et al, 1987), and cilazaprilat is known to be eliminated primarily by renal excretion (Whitehead et al, 1989). The ester rather than acid form of the drug has been developed in order to achieve good absorption characteristics, but the absolute bioavailability of cilazaprilat has not been assessed in man.…”

Section: Introductionmentioning

confidence: 99%

The pharmacokinetics and bioavailability of cilazapril in normal man.

Williams¹,

Brown²,

Rajaguru³

et al. 1989

Brit J Clinical Pharma

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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.

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“…Cilazaprilat Cmax was obtained within 1.5 to 2.0h, the concentrations subsequently decreasing with an apparent t'l2 of 8h. The total urinary recovery of cilazaprilat was 80 to 84%; CL and CLR in healthy subjects were 13.2 ± 7.1 and 4.6 ± 3.3 L/h, respectively (Fillastre et al 1989;Shionori et al 1989;Whitehead et al 1989).…”

Section: Cilazaprilmentioning

confidence: 97%

Pharmacokinetics of Newer Drugs in Patients with Renal Impairment (Part II)

Singlas

Fillastre

1991

Clinical Pharmacokinetics

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Cardiovascular diseases occur frequently in patients with renal failure. Any pharmacokinetic impairment in these diseases should be considered when individualizing drug therapy. The pharmacokinetics of new cardiovascular drugs in uraemic patients are reviewed: alpha- and beta-blocking agents, ACE inhibitors, centrally acting antihypertensive agents, calcium antagonists, antiarrhythmic agents and inotropic agents. Guidelines are proposed for adjustment of dosage regimens as a function of renal impairment. Renal or extrarenal elimination of drugs and their metabolites, and the activity of the latter, are taken into account. The disposition of new drugs such as flestolol, alacepril, delapril, propafenone, milrinone or enoximone, is not well documented in patients with renal failure. Further characterizations of the elimination of these compounds are needed and the potential therapeutic or toxic effects of the metabolites require evaluation to determine whether the dosage needs to be adjusted. Until such investigations are performed, those drugs should not be used in uraemic patients; if no therapeutic alternative is available, clinical controls are necessary at regular intervals. Relationships between pharmacological or therapeutic effects and drug plasma concentrations should be evaluated for such long term use drugs. The knowledge of a plasma concentration therapeutic window is important to provide information which will be useful in determining appropriate drug dosage in renal failure.

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Pharmacokinetics of intravenous cilazaprilat in normal volunteers.

Cited by 10 publications

References 6 publications

A pharmacokinetic study of cilazapril in elderly and young volunteers.

A pharmacokinetic study of cilazapril in elderly and young volunteers.

The pharmacokinetics and bioavailability of cilazapril in normal man.

Pharmacokinetics of Newer Drugs in Patients with Renal Impairment (Part II)

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