Enalapril maleate and a lysine analogue (MK‐521) in normal volunteers; relationship between plasma drug levels and the renin angiotensin system.

Biollaz, J.; Jl, Schelling; Combes, Bruno; Brunner, D. B.; Desponds, G; Brunner, Heinrich; Ulm, E H; Hichens, Martin; Gómez, Héctor W.

doi:10.1111/j.1365-2125.1982.tb01992.x

Cited by 112 publications

(37 citation statements)

References 11 publications

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“…The time course of MK-422 and MK-521 in serum closely paralleled their pharmacological and biochemical effects (Biollaz et al, 1982). In addition to the results of Biollaz et al (1982), Swanson et al (1981) reported an inverse relationship between plasma converting enzyme activity and the serum concentration of MK-422 in subjects who had received enalapril maleate.…”

Section: Discussionmentioning

confidence: 64%

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Enalapril maleate and a lysine analogue (MK‐521): disposition in man.

Ulm¹,

Hichens²,

Gómez³

et al. 1982

Brit J Clinical Pharma

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210

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1 The disposition of two angiotensin converting-enzyme inhibitor drugs was studied in normal volunteers. One drug was enalapril maleate (MK-421), which requires in vivo esterolysis to yield active inhibitor . The other was a lysine analogue of MK-422 (MK-521), which requires no bioactivation. 2 Absorption of enalapril maleate (10 mg, p.o.) was rapid, with peak serum concentrations of enalapril observed 0.5-1.5 h after administration. Based upon urinary recovery of total drug (enalapril plus MK-422), absorption was at least 61%. Bioactivation appeared to be largely post-absorptive. From the ratio of MK-422 to total drug in urine, the minimum extent of bioactivation was estimated at 0.7. 3 A similar dose of MK-521 was absorbed more slowly, reaching peak serum concentrations 6-8 h following drug administration. Minimum absorption, based upon urinary recovery, was 29%. 4 Serum concentration v time profiles for both drugs were polyphasic and exhibited prolonged terminal phases. 5 Recovery in urine and faeces of administered enalapril maleate (intact and as MK-422) was 94%. Recovery of MK-521 was 97%. These results indicate lack of significant metabolism of these agents, apart from the bioactivation of enalapril.

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Section: Discussionmentioning

confidence: 64%

“…This level of inhibition occurred about 1 h after enalapril maleate administration and about 2 h after MK-521 (Biollaz et al, 1982). From the serum concentration versus time profiles (Figures 2 and 3), the corresponding inhibitor concentrations were 20 and 18 nm.…”

Section: Discussionmentioning

confidence: 91%

Enalapril maleate and a lysine analogue (MK‐521): disposition in man.

Ulm¹,

Hichens²,

Gómez³

et al. 1982

Brit J Clinical Pharma

Self Cite

210

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“…6 - 10 Although 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.…”

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confidence: 99%

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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“…With most compounds, the components of the renin-angiotensin system (RAS) including ACE activity, angiotensin I and II and plasma renin activity have been determined before and during ACE inhibition. Whenever possible, these biochemical determinations have been correlated with measured plasma drug concentrations to establish a concentration-effect relationship (Biollaz et al, 1982;Bussien et al, 1985;Nussberger et al, 1987). The in vitro measurement of plasma ACE activity appeared to be a useful means to determine the degree of RAS blockade and has been used extensively for the purpose of characterizing pharmacokinetics although evidence is accumulating which suggests that it is not necessary to suppress ACE activity permanently to decrease blood pressure (Boomsma et al, 1981;Waeber et al, 1980).…”

Section: Introductionmentioning

confidence: 99%

“…In an attempt to characterize better the in vivo inhibition of ACE, we have calculated in the past several years the ratio of angiotensin II to angiotensin I measured in plasma (Biollaz et al, 1982). This parameter should actually reflect not only the enzymatic activity taking place in the plasma but also the conversion occurring in endothelial cells.…”

Section: Introductionmentioning

confidence: 99%