Steady-State Kinetics of Ramipril in Renal Failure

Schunkert, Heribert; Kindler, Jochen; Gassmann, Martin; Lahn, W.; Irmisch, R; Er, Debusmann; Ocón-Pujadas, J; Hg, Sieberth

doi:10.1097/00005344-198900133-00013

Cited by 23 publications

(5 citation statements)

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“…The half-life is also significantly increased in the elderly and in the presence of renal impairment. [5][6][7] Previous studies on the effects of ramipril in heart failure have shown that ramipril resulted in a reduced mortality. 8 However, the target dose of ramipril used was 5 mg twice daily.…”

Section: Introductionmentioning

confidence: 99%

Assessment of single versus twice daily dosing of ramipril by ambulatory blood pressure monitoring in patients similar to those included in the HOPE study

et al. 2007

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Ramipril has been used in twice daily dose of 5 mg in most heart failure trials, whereas the dose used in Heart Outcomes Prevention Evaluation (HOPE) study was 10 mg once at bedtime. The HOPE investigators in an ambulatory blood pressure (ABP) substudy observed a fall of nighttime but not daytime blood pressure (BP). We examined the effects of once daily ramipril 10 mg versus 5 mg twice a day. Twenty-nine patients were recruited based on the original criteria for the HOPE study and were given ramipril either in twice-daily dose (5 mg b.d.) or once daily (10 mg o.d.) each morning in randomized, prospective crossover trial. Twenty-four hour ABP recordings were taken just before commencement of ramipril therapy and after treatment with twicedaily and once-daily ramipril. Our results show that ramipril causes a significant reduction of BP over 24-h period as compared with baseline. The mean baseline ABP was 124/73 mm Hg, which reduced to 117/69 mm Hg for the twice-a-day regimen (Po0.001) and 115/68 mm Hg for the once a day regimen (Po0.001). Both regimes effectively lower BP to a similar extent. Ramipril causes significant BP reduction in both once-and twice-daily dosing. The fall in BP after daytime dosing is greater than that observed in the HOPE study (including ABP substudy). Once-daily dosing in the morning seems to be effective in causing a significant reduction in the ABP profile of patients at high-risk of a future vascular event.

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Section: Introductionmentioning

confidence: 99%

Assessment of single versus twice daily dosing of ramipril by ambulatory blood pressure monitoring in patients similar to those included in the HOPE study

et al. 2007

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“…Ramipril is a prodrug which is rapidly absorbed from the gastrointestinal tract and converted to its active metabolite ramiprilat, a dicarboxylic acid, by cleavage of an ester group [14]. These properties account for its potency and long duration of action [15,16]. In healthy volunteers a single oral dose of 5 mg ramipril reduced ACE activity by more than 70% relative to pretreatment values [17].…”

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confidence: 99%

Pharmacokinetics, pharmacodynamics and bioavailability of the ACE inhibitor ramipril

Griensven

Schoemaker

Cohen

et al. 1995

Eur J Clin Pharmacol

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The pharmacokinetics and pharmacodynamics of the prodrug ramipril and its active ACE-inhibiting metabolite ramiprilat were investigated in an open, randomised, three-way cross-over study in 12 healthy male volunteers. Subjects received 2.5 mg ramipril orally, 2.5 mg ramipril intravenously and 2.5 mg ramiprilat intravenously. The absolute bioavailability as judged by ramipril plasma AUC was 15%, by ramiprilat plasma AUC, 44%. Ramiprilat formation from intravenous ramipril was 53% and from oral ramipril 28%. Urinary recovery of oral ramipril was 23%, i.v. ramipril 49%, and i.v. ramiprilat 68% of the given dose. Maximum ACE inhibition was highest (100%) after i.v. ramiprilat; it was 99% after i.v. ramipril and 84% following oral ramipril. ACE inhibition over 24 h was highest after i.v. ramipril, 2% less with i.v. ramiprilat and 34% less with oral ramipril. Ramiprilat renal clearance was concentration dependent. The biological availability of ramipril can best be judged by ramiprilat AUC, urinary recovery of ramipril and metabolites, or ACE inhibition over 24 h. It is concluded that the bioavailability of oral ramipril seems to be in the range of 44-66%.

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“…Only a high ramiprilat concentration with a relevant blood alcohol concentration could be defined as remarkable in the discussed cases 8 and 9. Under the assumption that prescribed drug doses were taken by car drivers, the high ramiprilat levels could be explained only by the age or/and different diseases [19][20][21][22]. Without the assumption of the intake of prescribed drug doses, high ramiprilat concentrations could also be discussed as a result of an intake of an excessive drug dose.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the information was restricted to protocols provided by the police and no clinical data was available. Thus, high ramiprilat concentrations were interpreted on the basis of previous findings [19][20][21][22] and an assumption that therapeutic drug doses were taken [8,9]. This fact can be seen as a limitation of the data evaluation presented since we do not assume as likely but cannot also fully exclude that these high ramiprilat blood serum concentrations could be a result of an inappropriate dosing.…”

Section: Discussionmentioning

confidence: 99%

“…In general, according to the further literature, increased ramiprilat concentrations can be expected in the elderly and patients with renal impairment and heart failure [ 19 ]. In detail, even a ten times greater mean trough concentration was observed for patients with renal failure in comparison to healthy subjects [ 20 ]. On the other site, two separate studies demonstrated additionally that the maximal mean ramiprilat concentration in elderly (mean age ≥ 71 years) with normal renal function can be increased by 20% and 200% when compared to healthy young volunteers [ 19 , 21 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

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The analysis of ramipril/ramiprilat concentration in human serum with liquid chromatography-tandem mass spectrometry – interpretation of high concentrations for the purposes of forensic toxicology

Dziadosz

Rosenberger

Klintschar

et al. 2023

Forensic Sci Med Pathol

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Ramipril is a popular angiotensin-converting enzyme inhibitor applied in the treatment of hypertension. Its therapeutic effect is oriented on the concentration of the active metabolite ramiprilat. The information about toxic drug levels is missing in the literature. Therefore, the aim of this work was an indication of possible toxic ranges based on the analysis of real samples with high ramiprilat concentrations. For these purposes, an appropriate analytical LC–MS/MS method was developed and validated according to forensic guidelines and applied in the routine. Most real samples targeted for ramipril/ramiprilat were associated with the typical therapeutic drug range of 1–40 ng/mL described in the literature. However, higher drug levels with ramiprilat concentrations above 100 ng/mL could also be observed infrequently in cases of driving under the influence of drugs or attempted suicides. To the best of the author’s knowledge, this is the first time antemortem ramipril and ramiprilat concentrations associated with driving under the influence of drugs and suicide attempts were discussed from a forensic point of view. The collected data enabled an indication of the ramiprilat toxic concentration range from about 600 ng/mL to at least 3500 ng/mL. The toxic concentration range discussed can be applied in the forensic practice as a reference for future cases.

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Steady-State Kinetics of Ramipril in Renal Failure

Cited by 23 publications

References 0 publications

Assessment of single versus twice daily dosing of ramipril by ambulatory blood pressure monitoring in patients similar to those included in the HOPE study

Assessment of single versus twice daily dosing of ramipril by ambulatory blood pressure monitoring in patients similar to those included in the HOPE study

Pharmacokinetics, pharmacodynamics and bioavailability of the ACE inhibitor ramipril

The analysis of ramipril/ramiprilat concentration in human serum with liquid chromatography-tandem mass spectrometry – interpretation of high concentrations for the purposes of forensic toxicology

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