Hemodynamics, biochemical effects, and pharmacokinetics of the renin inhibitor remikiren in healthy human subjects

Kleinbloesem, Cornelis H.; Weber, Cornelia; Fahrner, Eva; Dellenbach, M.; Welker, H. A.; Schröter, Volkmar; Beiz, Gustav G

doi:10.1038/clpt.1993.74

Cited by 37 publications

(36 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The between subject variability of the oral pharmacokinetics of remikiren was high in all studies. There was, however, a very good correlation between the drug concentrations and the pharmacodynamic effect of the net inhibition of plasma renin activity in the plasma compartment in healthy male volunteers [14]. These in vivo results on plasma renin inhibition were in good agreement with the results found in vitro [8].…”

Section: Introductionsupporting

confidence: 80%

“…intersubject variability. This was already observed in healthy volunteers and was expected as a consequence of the high liver first-pass extraction of the compound [14]. Despite this high variability, there was a clear dose dependency in Cmax (study A and B) and AUC (study B).…”

Section: Discussionmentioning

confidence: 84%

“…Long lasting ascribed to accumulation of bradykinin or substance P reduction in blood pressure has been shown in hyperwhich are both inactivated by ACE in vivo [2,3,4]. In tensive marmosets and squirrel monkeys [8] as well as contrast, blocking the renin angiotensin system by in hypertensive patients [10,11,12] in healthy volunteers [13,14,15] showed a high systemic plasma clearance (900 ml min-1), a large volume of distribution (70 1) and a very low oral bioavailability (around 1%), which is probably due to the high liver first-pass extraction of the compound. The between subject variability of the oral pharmacokinetics of remikiren was high in all studies.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Multiple dose pharmacokinetics and concentration effect relationship of the orally active renin inhibitor remikiren (Ro 42–5892) in hypertensive patients

Weber

Birnböck

Leube

et al. 1993

Brit J Clinical Pharma

Self Cite

View full text Add to dashboard Cite

1 Three double-blind, randomized, placebo controlled, multiple oral dose studies in patients with mild to moderate hypertension were performed to study tolerability, pharmacodynamics and pharmacokinetics of remikiren. Doses of 100-800 mg remikiren or placebo were given over 8 days to altogether 144 patient volunteers. In some cases (n = 46) single i.v. doses of 100 mg were administered 4 h after the last oral dose. Plasma remikiren concentrations, plasma renin activity and immunoreactive renin concentrations were measured. Pharmacokinetic parameters were estimated using model independent techniques and the concentration-effect relationship was evaluated using population pharmacometric methods. 2 In most patients no distinct absorption and disposition phase could be identified, since plasma concentrations fluctuated widely over a period of approximately 10 h. Peak plasma concentrations (Cmax) were achieved within 0.25-2 h postdose. Mean Cmax values (on the first and last day of oral treatment) were in the magnitude of 4-6 ng ml-1 (200 mg), 23-27 ng ml-1 (300 mg), 65-83 ng ml-1 (600 mg) and 47-48 ng ml-1 (800 mg). Cmax and AUCO-t values were clearly different for different doses within single studies. Intersubject variability in pharmacokinetic parameters was much higher than intrasubject variability. No drug accumulation in plasma was apparent. 3 Inhibition of the angiotensin I production rate correlated well with plasma drug concentrations according to the Emax-model. An IC50 value of 0.5 ng ml-1 (0.8 nM)was estimated. No correlation between blood pressure changes on the last day of oral treatment and either plasma remikiren concentrations or plasma renin inhibition was found.

show abstract

Section: Introductionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Multiple dose pharmacokinetics and concentration effect relationship of the orally active renin inhibitor remikiren (Ro 42–5892) in hypertensive patients

Weber

Birnböck

Leube

et al. 1993

Brit J Clinical Pharma

Self Cite

View full text Add to dashboard Cite

show abstract

“…In agreement with the known regulatory mechanisms governing renin release, immunoreactive renin increased after remikiren due to interruption of negative feedback control of plasma renin by reduced angiotensin II levels.44 This effect persisted throughout the period of drug administration, confirming the potency of this renin inhibitor when administered intravenously in humans. 32,44 Enalaprilat also caused biochemical changes compatible with blockade of the renin-angiotensin system; plasma renin activity and immunoreactive renin increased as expected from a loss of negative feedback control of plasma renin by reduced angiotensin II levels, but completeness of converting enzyme blockade is more difficult to determine without measurement of converting enzyme activity or plasma angiotensin II concentrations. However, indirect evidence suggests that enalaprilat provided complete blockade of the renin-angiotensin system.…”

Section: Hormonal Responsesmentioning

confidence: 99%

“…This dosage regimen was chosen based on previous studies in volunteers showing rapid, complete, and long-lasting renin inhibition after similar intravenous doses. 32 Enalaprilat was administered as a 9 gg/kg intravenous bolus followed by infusion of 1.5 ,ug/kg per hour. This dosage regimen was chosen based on the manufacturer's recommendation and published data showing that similar doses induced rapid hemodynamic changes and complete inhibition of angiotensinconverting enzyme.…”

Section: Hormone Determinationsmentioning

confidence: 99%

Angiotensinergic versus nonangiotensinergic hemodynamic effects of converting enzyme inhibition in patients with chronic heart failure. Assessment by acute renin and converting enzyme inhibition.

et al. 1994

View full text Add to dashboard Cite

BACKGROUND The contribution of nonangiotensinergic effects of converting enzyme inhibitors to their hemodynamic effects in patients with chronic heart failure is not clear. A comparison of the effects of renin and converting enzyme inhibition should help to clarify this issue. METHODS AND RESULTS Thirty-six patients with chronic heart failure (New York Heart Association class II or III) were randomly assigned to receive double-blind either intravenous placebo, the renin inhibitor remikiren, or the converting enzyme inhibitor enalaprilat followed by coinfusion of a second placebo infusion, the addition of remikiren to enalaprilat, or the addition of enalaprilat to remikiren, respectively. Systemic hemodynamics (Swan-Ganz and radial artery catheters) were measured before (rest and submaximal recumbent bicycle ergometry), during (rest), and at the end (rest and exercise) of each 45-minute single- or combination-infusion period. Placebo did not change hemodynamics or renin activity. Effective inhibition of the renin-angiotensin system by remikiren and enalaprilat was indicated by increases of plasma immunoreactive renin together with rapid and complete inhibition of renin activity after remikiren and an increase after enalaprilat (all P < or = .05). Remikiren and enalaprilat rapidly and to a similar extent reduced resting blood pressure through a reduction of systemic vascular resistance, and these changes were significantly correlated to baseline plasma renin activity. Both compounds also decreased pulmonary artery, pulmonary capillary wedge, and right atrial pressures to a similar extent (P < .05). During exercise, pulmonary capillary wedge and right atrial pressures were equally reduced and stroke volume index was increased with remikiren and enalaprilat (P < .05) for both). The combination of converting enzyme with renin inhibition or vice versa did not cause additional hemodynamic changes. CONCLUSIONS Specific renin inhibition in patients with chronic heart failure produces short-term hemodynamic effects that are almost indistinguishable from those of converting enzyme inhibition. This finding and the lack of additional effects of converting enzyme inhibition added to renin inhibition suggest that nonangiotensinergic effects of converting enzyme inhibitors do not play a significant role in their short-term hemodynamic effects in patients with chronic heart failure.

show abstract

Pharmacokinetics and pharmacodynamics of CI-992 following intravenous and oral administration to cynomolgus monkeys

Cook¹,

Burger²,

Michniewicz³

et al. 1998

Biopharm. Drug Dispos.

View full text Add to dashboard Cite

Hemodynamics, biochemical effects, and pharmacokinetics of the renin inhibitor remikiren in healthy human subjects

Abstract: Remikiren is a potent inhibitor of renin in humans with long-lasting effects after both intravenous and oral administration.

Cited by 37 publications

References 0 publications

Multiple dose pharmacokinetics and concentration effect relationship of the orally active renin inhibitor remikiren (Ro 42–5892) in hypertensive patients

Multiple dose pharmacokinetics and concentration effect relationship of the orally active renin inhibitor remikiren (Ro 42–5892) in hypertensive patients

Angiotensinergic versus nonangiotensinergic hemodynamic effects of converting enzyme inhibition in patients with chronic heart failure. Assessment by acute renin and converting enzyme inhibition.

Pharmacokinetics and pharmacodynamics of CI-992 following intravenous and oral administration to cynomolgus monkeys

Contact Info

Product

Resources

About