Add time:08/01/2019         Source:sciencedirect.com

A study was made of the excretion of radioactivity in bile of male rats after administration of orphenadrine hydrochloride and tofenacin hydrochloride in labelled forms. In bile fistula rat it was found, particularly after intravenous administration, that biliary excretion was considerable: after five hours 31 to 48% of the radioactivity had been excreted in the bile. In normal rats, total biliary elimination exceeded urinary elimination. A study of the radioactivity in the blood, liver and bile showed two phases of concentration: first, from blood to liver, more than a 100-fold concentration was achieved and second from liver to bile, the concentration increased more than 5 times. When 10 mg/kg doses of the labelled compounds were administered i.v. the approximate points of time at which maximum concentrations were found in liver and bile were 10 and 20 min after administration, while in the blood maximum concentration was reached immediately after the injection. A compartment model is proposed to explain various aspects of the time course of biliary excretion of these drugs in bile fistula rats. Analytical investigations of orphenadrine metabolites in rat bile showed that only minor amounts of the compound were excreted unchanged or in the form of free (non-conjugated) metabolites; evidence was obtained for major excretion in the form of glucuronides and probably sulfates of aromatic hydroxylated orphenadrine metabolites. The biotransformations promoted excretion in the bile, as evidenced by the bile collected in the first five minutes after i.v. dosage; in that period conjugates were already dominant and pretreatment with the metabolic inhibitor proadifen produced a significant decrease in biliary excretion of radioactivity over 1 hr after administration - an effect which could not be related to competition. There is strong evidence that compounds of the type studied undergo enterohepatic circulation.

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