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Pharmacokinetics and Metabolism Following oral administration, fosinopril (the prodrug) is absorbed slowly. The absolute absorption of fosinopril averaged 36% of an oral dose. The primary site of absorption is the proximal small intestine (duodenum/ jejunum). While the rate of absorption may be slowed by the presence of food in the gastrointestinal tract, the extent of absorption of fosinopril is essentially unaffected. Fosinoprilat is highly protein-bound (approximately 99.4%), has a relatively small volume of distribution, and has negligible binding to cellular components in blood. After single and multiple oral doses, plasma levels, areas under plasma concentra-tion-time curves (AUCs) and peak concentrations (Cmaxs) are directly proportional to the dose of fosinopril. Times to peak concentrations are independent of dose and are achieved in approximately 3 hours. After an oral dose of radiolabeled fosinopril, 75% of radioactivity in plasma was present as active fosinoprilat, 20-30% as a glucuronide conjugate of fosinoprilat, and 1-5% as a p-hydroxy metabolite of fosinoprilat. Since fosinoprilat is not biotrans-formed after intravenous administration, fosinopril, not fosinoprilat, appears to be the precursor for the glucuronide and p-hydroxy metabolites. Text Continues Below
In rats, the p-hydroxy metabolite of fosinoprilat is as potent an inhibitor of ACE as fosinoprilat; the glu-curonide conjugate is devoid of ACE inhibitory activity. After intravenous administration, fosinoprilat was eliminated approximately equally by the liver and kidney. After oral administration of radiolabeled fosinopril, approximately half of the absorbed dose is excreted in the urine and the remain-der is excreted in the feces. In two studies involving healthy subjects, the mean body clearance of intravenous fosinoprilat was between 26 and 39 mL/ min. Page: << Prev | 1 | 2 | 3 | 4 | 5 | Next >>
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