Pharmacokinetics of repeated single oral doses of enalapril maleate (mk‐421) in normal volunteers

Till, Alice E.; Gómez, Héctor W.; Hichens, Martin; Bolognese, James A.; McNabb, W R; Brooks, Baruch; Noormohamed, FH; Lant, A. F.

doi:10.1002/bdd.2510050309

Cited by 87 publications

(47 citation statements)

References 5 publications

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“…Thereafter, in accordance with the findings and recommendations of Till et al 20 and of Francis et al, 13 a one-compartment model with saturable protein binding was found to produce satisfactory fits to the data. In addition, by using a number of criteria of goodness of fit, a unified approach fitting this model simultaneously to acute and steady-state data was found to be superior to both the original "conventional" approach and to independent fitting for each study day.…”

Section: Pharmacokinetic Analysissupporting

confidence: 79%

“…Consistent with the observations of Till et al, 20 a conventional pharmacokinetic model could not be used to satisfactorily describe all the features of the disposition, particularly the accumulation of enalaprilat during long-term therapy. A "physiologically realistic" model, based on the putative saturable binding of drug to ACE, 13 was found to be appropriate for describing both the pharmacokinetics of enalaprilat and the kinetic-dynamic relations.…”

Section: Discussionmentioning

confidence: 64%

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Kinetic-dynamic relations and individual responses to enalapril.

et al. 1990

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Pharmacoklnetic and phannacodynamic variability largely account for interindividual differences in the response to antihypertensive drugs including angiotensin converting enzyme inhibitors. The factors determining the response to enalapril have been investigated in a placebo-controlled study in essential hypertension. The effects of placebo, the initial dose of enalapril, and long-term (1 and 6 weeks) treatment with enalapril were studied in 13 subjects. By using an integrated kinetic-dynamic model that incorporates a parameter for saturable protein binding, individual responses for blood pressure reduction and angiotensin converting enzyme inhibition were characterized in terms of the maximum effect (E^J and the drug concentration required to produce 50% of E M (0,50). In individual subjects, plasma enalaprilat concentrations could be correlated with falls in blood pressure and changes in plasma angiotensin converting enzyme activity. For the group, E^, was -46.1 ±16.5 and -19.7 ±3.8 mm Hg for systolic and dlastolic blood pressure, respectively, and the corresponding C,50 values were 66.1 ±20.2 and 61.6 ±22.5 ng/ml. For angiotensin converting enzyme inhibition, £ " , (%) and C.50 (ng/ml) were, respectively, 102.4±5 and 19.8±13 after the first dose, 103±5 and 33.4±20J after 1 week, and 101 J±2.2 and 31 J±18.9 after 6 weeks. There was no relation between the responsiveness to enalapril ( E^ or C.50) and patient age or plasma renin activity, but there was a significant positive correlation between E^ and the pretreatment blood pressure. In individual subjects, E^ (first dose) was directly correlated with E mM1 after 1 and 6 weeks. This study, which incorporated kinetic as well as dynamic information to characterize the antihypertensive response to enalapril, has identified enalaprilat concentration-effect relations in individual hypertensive subjects. 3 Qinical studies have shown large interindividual differences in the effect of an ACE inhibitor on blood pressure and the renin-angiotensin system, particularly after the first dose, but little attempt has been made to quantify and optimize the response in individual subjects. 4 There is some evidence that reduction of blood pressure and inhibition of plasma ACE activity are dose-dependent, 5 " 7 but no consistent concentrationeffect relation has been established between plasma drug (or active metabolite) concentration and blood pressure reduction or ACE inhibition. Received May 1, 1989; accepted in revised form October 30, 1989. this is likely to reflect the wide range of intersubject variability in pharmacokinetic responses, particularly when group data are evaluated, there is preliminary evidence that concentration-effect relations for ACE inhibitors can be more readily identified when individual subjects are considered. -13This study uses integrated pharmacokineticpharmacodynamic modeling 14 to investigate and characterize the antihypertensive responses and concentration-effect relations during acute and chronic treatment with enalapril in patients with esse...

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Section: Pharmacokinetic Analysissupporting

confidence: 79%

Section: Discussionmentioning

confidence: 64%

Kinetic-dynamic relations and individual responses to enalapril.

et al. 1990

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“…The extent of this would relate to amounts of the enzyme in blood and would not reflect the dose of the drug (Till et al, 1984). The effects of this component on serum enalaprilat concentrations is only readily apparent at low concentrations (less than 1-2 ng…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of enalapril in normal subjects and patients with renal impairment.

Kelly¹,

Doyle²,

Donohue³

et al. 1986

Brit J Clinical Pharma

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1 The pharmacokinetics of enalaprilat were studied after administration of single and multiple doses of enalapril maleate to people with normal and impaired renal function. 2 Renal impairment was associated with higher serum concentrations of enalaprilat, longer times to peak concentrations, slower decline of serum concentrations and with reduced urinary elimination. Urinary elimination of enalaprilat was closely related to renal function.3 In patients with severe renal impairment (GFR values below 30 ml min7l 1.73 m-2) significantly smaller doses of enalapril maleate will be required than in patients with normal or less severely impaired renal function.

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“…Information is available concerning the absorption, metabolism and elimination of this compound as administered to normal healthy volunteers (Ulm et al, 1982(Ulm et al, , 1983Till et al, 1984;Irvin et al, 1984). Absorption of drug is approximately 60% of the administered dose; the bioavailability of the active species (enalaprilat) is approximately 40% of the dose administered.…”

Section: Introductionmentioning

confidence: 99%

The pharmacokinetics of enalapril in hospitalized patients with congestive heart failure.

Dickstein

Till

Aarsland

et al. 1987

Brit J Clinical Pharma

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1 The pharmacokinetics of the converting enzyme inhibitor, enalapril, were studied in an open, randomized, balanced crossover design in 12 hospitalized patients with stable, chronic congestive heart failure (CHF). Enalapril maleate is a prodrug requiring in vivo hepatic esterolysis to yield the active diacid inhibitor enalaprilat. 2 CHF results in changes in regional blood flow that may affect the gastrointestinal absorption, hepatic hydrolysis and renal excretion of enalapril and enalaprilat. 3 In order to evaluate the pharmacokinetics of enalapril in CHF, the following treatments were given: enalapril maleate 10 mg orally, enalapril maleate 5 mg intravenously and enalaprilat 5 mg intravenously. Each dose was followed by a 72 h period with frequent blood sampling and fractionated urine collection for the radioimmunoassay of enalaprilat, before and after sample hydrolysis.4 Mean absorption for the oral dose was 69%, hydrolysis 55%, bioavailability 38%, urinary recovery 77% and estimated first-pass effect 10%. 5 The results were compared with available data in normal subjects. After oral administration of 10 mg enalapril maleate, the extent of absorption, the degree of hydrolysis and the bioavailability in CHF patients appear to be similar to those in normals with differences less than 10%. The rate of absorption and hydrolysis appear to be slightly slower in CHF. The serum concentrations of enalaprilat were consistently greater in CHF and maximal concentrations were reached at 6 h in CHF as compared to 4 h in normal subjects. 6 We conclude that the presence of CHF does not appreciably alter the pharmacokinetic behaviour of enalapril. The observed differences may be associated with age as well as the disease state.

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Pharmacokinetics of repeated single oral doses of enalapril maleate (mk‐421) in normal volunteers

Cited by 87 publications

References 5 publications

Kinetic-dynamic relations and individual responses to enalapril.

Kinetic-dynamic relations and individual responses to enalapril.

Pharmacokinetics of enalapril in normal subjects and patients with renal impairment.

The pharmacokinetics of enalapril in hospitalized patients with congestive heart failure.

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