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Blood concentrations of ramipril and ramiprilat increase with increased dose, but are not strictly dose-pro-portional. The 24-hour AUC for ramiprilat, however, is dose-proportional over the 2.5Ð 20 mg dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when 5 mg of oral ramipril was compared with the same dose of ramipril given intravenously. Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase, terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a large peripheral compartment and subsequent binding to both plasma and tissue ACE, has a half-life of 2Ð 4 hours. Because of its potent binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elim-ination phases. The apparent elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9Ð 18 hours. The terminal elimination phase has a prolonged half-life (> 50 hours) and probably represents the binding/ dissociation kinetics of the ramiprilat/ ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of ramipril 5Ð 10 mg, the half-life of ramiprilat concentrations within the ther-apeutic range was 13Ð 17 hours. After once-daily dosing, steady-state plasma concentrations of ramiprilat are reached by the fourth dose. Text Continues Below
Steady-state concentrations of ramiprilat are somewhat higher than those seen after the first dose of ALTACE, especially at low doses (2.5 mg), but the difference is clinically insignificant. In patients with creatinine clearance less than 40 ml/ min/ 1.73m 2 , peak levels of ramiprilat are approximate-ly doubled, and trough levels may be as much as quintupled. In multiple-dose regimens, the total exposure to ramiprilat (AUC) in these patients is 3Ð 4 times as large as it is in patients with normal renal function who receive similar doses. Page: << Prev | 1 | 2 | 3 | 4 | 5 | Next >>
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