Pilot Study on Bioavailability of Coumarin and 7‐Hydroxycoumarin upon Peroral Administration of Coumarin in a Sustained‐Release Dosage Form

Abstract

Prolonged‐release tablets containing coumarin were compared to intravenous and peroral administration of coumarin solution in man. Unchanged coumarin, the Phase I metabolite 7‐hydroxycoumarin, and the Phase II metabolite 7‐hydroxycoumarin glucuronide were determined in whole blood. Upon peroral administration, only approximately 1 per cent coumarin was found unchanged in the systemic circulation. However, the amount of the glucuronide found indicates complete absorption with extensive first‐pass effect. When the prolonged‐release dosage form was compared to the peroral solution, the extent of bioavailability of coumarin was 35 per cent, whereas the 7‐hydroxycoumarin glucuronide was totally available. This supports the hypothesis that coumarin might be a prodrug and 7‐hydroxycoumarin the active moiety. The drug liberation of coumarin from the sustained‐release tablets follows first‐order kinetics. A linear correlation was found between per cent of drug released in vitro and the area under the concentration‐time curve, AUC (0‐t), of total 7‐hydroxycoumarin (7HC + 7HCG).