Concentration effect modelling with converting enzyme inhibitors in man [letter]

Kelman, Andrew W.; Reid, JL; Millar, J. A.

doi:10.1111/j.1365-2125.1983.tb01542.x

Cited by 16 publications

(7 citation statements)

References 8 publications

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“…Elimination half life (t½) of the terminal phase was obtained by log-linear regression of plasma levels at 48, 72 and 96 h. Differences in the AUC for percentage inhibition of ACE among the groups of treatment were tested by one way ANOVA, completed by a Newman Keuls test in case of a significant group effect. The relationship between plasma zabiciprilat concentrations and percentage inhibition of plasma ACE activity in individuals was fitted to a sigmoid Ima, model (Hill equation) using a non-linear least squares procedure (Kelman et al, 1983). Inhibition I, is related to plasma concentration, C, by the equation…”

Section: Pharmacokinetic and Statistical Analysismentioning

confidence: 99%

Pharmacodynamic, pharmacokinetic and humoral effects of oral zabicipril, an angiotensin converting enzyme inhibitor in normotensive man.

Macdonald

Hughes

Lees

et al. 1990

Brit J Clinical Pharma

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1. Zabicipril, S9650, a new angiotensin converting enzyme inhibitor, was administered to salt‐replete, normotensive males in single doses of up to 10 mg. 2. The safety, tolerance and dose‐response relationship with regard to inhibition of plasma ACE activity were characterised initially in an open, pilot, dose‐finding study in 12 subjects and further explored in a double‐blind, parallel group, placebo controlled study in another 30 subjects. 3. The drug was generally well tolerated and produced no change in routine haematology or serum biochemistry tests. 4. Dose related (0.03 to 10 mg) inhibition of plasma converting‐ enzyme was observed, with 2.5 mg of zabicipril producing over 90% inhibition at 4 h and 60% at 24 h. 5. There were no significant changes in blood pressure or heart rate in normotensive subjects over the dose range studied. 6. A dose related rise in plasma renin activity and angiotensin I was observed. No dose related reduction in plasma aldosterone was observed. 7. These initial studies suggest that zabicipril is a well tolerated inhibitor of converting enzyme with near maximal inhibitory effect occurring at a dose of 2.5 mg. Further exploration of the dose range after single and multiple doses is indicated.

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Section: Pharmacokinetic and Statistical Analysismentioning

confidence: 99%

Pharmacodynamic, pharmacokinetic and humoral effects of oral zabicipril, an angiotensin converting enzyme inhibitor in normotensive man.

Macdonald

Hughes

Lees

et al. 1990

Brit J Clinical Pharma

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“…Comparisons were made by Student's t-test for unpaired data where appropriate. The relationship between plasma enalaprilat and percentage (%) inhibition of plasma ACE activity in individuals was described by the Hill equation (Hill, 1910) using the method described by Kelman et al (1983). Inhibition, I, is related to plasma concentration, C, by the equation…”

Section: Pharmacokinetic and Statistical Analysismentioning

confidence: 99%

Age and the pharmacokinetics of angiotensin converting enzyme inhibitors enalapril and enalaprilat.

Hockings¹,

Aa²,

Reid³

1986

Brit J Clinical Pharma

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The pharmacokinetics of angiotension converting enzyme (ACE) inhibitors enalapril (10 mg orally) and its active metabolite, enalaprilat (10 mg intravenously) were studied in nine young healthy volunteers aged 22‐30 years and nine sex matched elderly subjects aged 65‐73 years. After both drugs, a biexponential curve was fitted to the decline in plasma enalaprilat concentration. Area under the plasma concentration‐time curve (AUC) was greater in the elderly for both drugs. Clearance (CL) and clearance/bioavailability (CL/F) were less in the elderly for enalaprilat and enalapril, respectively. There was no difference in F between young (0.62 +/‐ 0.16) and elderly subjects (0.61 +/‐ 0.15). Enalaprilat CL and enalapril CL/F were significantly and positively correlated to endogenous creatinine clearance. There was a significant difference in the weight corrected volume of distribution at steady state after enalaprilat between the young and elderly (P less than 0.02). The relationship between plasma enalaprilat concentrations and percentage ACE inhibition, using the Hill equation, showed no difference in the sensitivity to ACE inhibition between the young and the elderly group. The pharmacokinetic differences observed are likely to be related to an age dependent decline in renal function as well as changes in body composition. Kinetic differences partly explain the greater pharmacodynamic response in the elderly.

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“…In many instances the accumulation of drug is such that the very earliest phases of drug accumulation and ACE inhibition are not well described even in oral dosing studies (Francis et al, 1987). Similar non linear relationships have been described where in vivo ACE inhibition is defined using angiotensin peptide ratios (Biollaz et al, 1982) although the exact description of the observed data is a matter of debate (Kelman et al, 1983). Preliminary studies using low dose intravenous infusions of ACE inhibitors have suggested that a sigmoid drug accumulation profile in venous plasma is evident which is best described by non linear saturable binding in which the pharmacokinetic model incorporates terms indicative of the proportions of drug bound to both plasma and tissue ACE (Lees et al, 1989).…”

Section: Kininase II Inhibitionmentioning

confidence: 88%

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1991

Brit J Clinical Pharma

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Concentration effect modelling with converting enzyme inhibitors in man [letter]

Cited by 16 publications

References 8 publications

Pharmacodynamic, pharmacokinetic and humoral effects of oral zabicipril, an angiotensin converting enzyme inhibitor in normotensive man.

Pharmacodynamic, pharmacokinetic and humoral effects of oral zabicipril, an angiotensin converting enzyme inhibitor in normotensive man.

Age and the pharmacokinetics of angiotensin converting enzyme inhibitors enalapril and enalaprilat.

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