Altace - Clinical Pharmacology

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Pharmacokinetics and Metabolism

Following oral administration of ALTACE, peak plasma concentrations of ramipril are reached within one hour. The extent of absorption is at least 50Ð 60% and is not significantly influenced by the presence of food in the GI tract, although the rate of absorption is reduced. In a trial in which subjects received ALTACE capsules or the contents of identical capsules dissolved in water, dissolved in apple juice, or suspended in apple sauce, serum ramiprilat levels were essentially unrelat-ed to the use or nonuse of the concomitant liquid or food. Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid metabolite, ramiprilat.

Peak plasma concentrations of ramiprilat are reached 2Ð 4 hours after drug intake. The serum protein binding of ramipril is about 73% and that of ramiprilat about 56%; in vitro, these percentages are independent of con-centration over the range of 0.01 to 10µg/ ml.

Ramipril is almost completely metabolized to ramiprilat, which has about 6 times the ACE inhibitory activity of ramipril, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which are inactive. After oral administration of ramipril, about 60% of the parent drug and its metabolites is eliminated in the urine, and about 40% is found in the feces. Drug recovered in the feces may represent both biliary excretion of metabolites and/ or unabsorbed drug, however the proportion of a dose elim-inated by the bile has not been determined. Less than 2% of the administered dose is recovered in urine as unchanged ramipril.

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).