RESUMO
Intravenous, oral and intraportal doses of diperdipine were given to bile duct cannulated dogs in order to assess the impact of first pass effect on the pharmacokinetics of this compound. After intravenous and oral doses, absolute bioavailability was calculated to be 18.7%. Biliary excretion accounted for about 0.1% of the total clearance of diperdipine and did not contribute to the overall elimination of the drug. After intraportal administration, the bioavailable fraction of diperdipine was increasing up to 44.3% suggesting a prehepatic site of loss of the drug. This was also substantiated by the fact that after oral administration a lesser fraction was excreted in the bile, than after the intraportal dose. The drug was highly bound to plasma proteins (greater than 96%) and was largely distributed in the blood cells for which a concentration dependent process was observed.
Assuntos
Bile/metabolismo , Proteínas Sanguíneas/metabolismo , Nitrendipino/análogos & derivados , Administração Oral , Animais , Bile/química , Cateterismo , Cães , Injeções Intravenosas , Masculino , Nitrendipino/administração & dosagem , Nitrendipino/farmacocinética , Nitrendipino/urina , Ligação Proteica , Fatores de TempoRESUMO
After oral administration of [14C] felodipine (27.5mg) to 4 healthy volunteers, 6 main urinary metabolites were identified by gas chromatography-mass spectrometry. The compounds were isolated by solvent extraction at pH 2.2 and silylated prior to analysis. They were formed by dehydrogenation of felodipine followed by ester hydrolysis, hydroxylation of the alkyl groups and conjugation. These metabolites were excreted both as free acids and as conjugates accounting on average for 37% of the excreted amount (23% of the dose). A specific liquid chromatographic assay with radioactive detection was developed to determine the acidic metabolites in all collected samples. The urinary excretion rate declined biphasically for the mono-acids III and IV, whereas the excretion rates of metabolites VI, VII and VIII, formed via aliphatic hydroxylation, were better fitted to equations of first-order processes.