Abstract
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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References
Burris JF (1991) The effect of ramipril on ambulatory blood pressure: a multicenter trial. J Cardiovasc Pharmacol 18 [Suppl 2]:131–133
Bauer B, Lorenz H, Zahlten R (1989) An open multicenter study to assess the long-term efficacy, tolerance, and safety of the oral angiotensin converting enzyme inhibitor ramipril in patients with mild to moderate essential hypertension. J Cardiovasc Pharmacol 13 [Suppl 3]:70–74
Cushman DW, Wang FL, Fung WC, Grover GJ, Harvey CM, Scalese RJ, Mitch SL, Deforrest JM (1989) Comparisons in vitro, ex vivo, and in vivo of the actions of seven structurally diverse inhibitors of angiotensin converting enzyme (ACE). Br J Clin Pharmacol 28:115S-131S
Schunkert H, Kindler J, Gassmann M, Lahn W, Irmisch R, Ritz E, Debusmann EK, Pujadas JO, Koch KM, Sieberth HG (1989) Pharmacokinetics of ramipril in hypertensive patients with renal insufficiency. Eur J Clin Pharmacol 37:249–256
Al-Nahhas AM, Nimmon CC, Britton KE, Carroll MJ, Al-Janabi MA, Solanki K, Bomanji J (1990) The effect of ramipril, a new angiotensin-converting enzyme inhibitor, on cortical nephron flow and effective renal plasma flow in patients with essential hypertension. Nephron 54:47–52
Kindler J, Schunkert H. Gassmann M, Lahn W, Irmisch R, Debusmann ER, Ocón-Pujadas J, Ritz E, Sieberth HG (1989) Therapeutic efficacy and tolerance of ramipril in hypertensive patients with renal failure. J Cardiovasc Pharmacol 13 [Suppl 3]:55–58
Hosie J, Meredith P (1991) The pharmacokinetics of ramipril in a group of ten elderly patients with essential hypertension. J Cardiovasc Pharmacol 18 [Suppl 2]:125–127
Gerckens U, Grube E, Mengden T, Sigel H, Wagner WL, Lahn T, Irmisch R, Metzger H (1989) Pharmacokinetic and pharmacodynamic properties of ramipril in patients with congestive heart failure (NYHA III–IV). J Cardiovasc Pharmacol 13 [Suppl 3]:49–51
Crozier IG, Ikram H, Nicholls MG, Jans S (1989) Global and regional hemodynamic effects of ramipril in congestive heart failure. J Cardiovasc Pharmacol 14:688–693
Schreiner M, Berendes B, Verho M, Langley A, Cairns V (1991) Antihypertensive efficacy, tolerance and safety of long-term treatment with ramipril in patients with mild-to-moderate essential hypertension. J Cardiovasc Pharmacol 18 [Suppl 2]:137–140
Carré A, Vasmant D, Elmalem J, Thiéry P (1991) Tolerability of ramipril in a multicenter of mild-to-moderate hypertension in general practice. J Cardiovasc Pharmacol 18 [Suppl 2]:141–143
Becker RHR, Baldes L, Treudler M (1989) Loop diuretics combined with an ACE inhibitor for treatment of hypertension: a study with furosemide, piretanide, and ramipril in spontaneously hypertensive rats. J Cardiovasc Pharmacol 13 [Suppl 3]:35–39
Heidbreder D, Froer K-L, Bauer B, Cairns V, Breitstadt A (1991) Efficacy and safety of ramipril in combination with hydrochlorothiazide: results of a long-term study. J Cardiovasc Pharmacol 18 [Suppl 2]:169–173
Vasmant D, Bender B (1989). The renin-angiotensin system and ramipril, a new converting enzyme inhibitor. J Cardiovasc Pharmacol 14 [Suppl 4]:46–52
Schunkert H, Kindler J, Gassmann M, Lahn W, Irmisch R, Debusmann ER, Ocón-Pejadas J Sieberth HG (1989) Steady-state kinetics of ramipril in renal failure. J Cardiovasc Pharmacol 13 [Suppl 3]:52–54
Grima M, Welsch C, Michel B, Barthelmebs M, Imbs J-L (1991) In vitro tissue potencies of converting enzyme inhibitors. Prodrug activation by kidney esterase. Hypertension 17:492–496
Sugimoto K, Kumagai Y, Tateishi T, Seguchi H, Ebihara A (1989) Effects on autonomic function of a new angiotensin converting enzyme inhibitor, ramipril. J Cardiovasc Pharmacol 13 [Suppl 3]:40–45
Schnaper HW (1991) Dose-response relationship of ramipril in patients with mild-to-moderate hypertension. J Cardiovasc Pharmacol 18 [Suppl 3]:128–130
Todd PA, Benfield P (1990) Ramipril. A review of its pharmacological properties and therapeutic efficacy in cardiovascular disorders. Drugs 1:110–135
Witte PU, Irmisch R, Hajdù P, Metzger H (1984) Pharmacokinetics and pharmacodynamics of a novel orally active angiotensin converting enzyme inhibitor (HOE 498) in healthy subjects. Eur J Clin Pharmacol 27:577–581
Eckert HG, Muenscher G, Oekonomopulos R, Strecker H, Urbach H, Wissmann H (1985) A radioimmunoassay for the angiotensin converting enzyme inhibitor ramipril and its active metabolite. Arzneimittelforschung/Drug Res 35:1251–1256
Schmidt D, Keller A (1985) Eine empfindliche Methode zur Bestimming des ACE-Hemmers HOE 498 und dessen Metaboliten in Humanurin mittels Capillarsäulen-Gas-Chromatographie. Fresenius Anal Chem 320:731
Rosenthal J, Buehler G, Koenig W, Rangoonwala B (1991) Effect of angiotensin-converting enzyme inhibition on human tissue renin. J Cardiovasc Pharmacol 18 [Suppl 2]:122–124
Williams PEO, Brown AN, Rajaguru S, Francis RJ, Walters GE, McEwen J, Durnin C (1989) The pharmacokinetics and bioavailability of cilizapril in normal man. Br J Clin Pharmacol 27 [Suppl]:181–188
Hockings N, Ajayi AA, Reid JL (1986) Age and the pharmacokinetics of angiotensin converting anzyme inhibitors enalapril and enalaprilat. Br J Clin Pharmacol 21:341–348
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van Griensven, J.M.T., Schoemaker, R.C., Cohen, A.F. et al. Pharmacokinetics, pharmacodynamics and bioavailability of the ACE inhibitor ramipril. Eur J Clin Pharmacol 47, 513–518 (1995). https://doi.org/10.1007/BF00193704
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DOI: https://doi.org/10.1007/BF00193704