Active transport of chlorothiazide into bile

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Abstract
The organic acid chlorothiazide, administered intravenously (20 mg/kg) to rats with ligated renal pedicles, rapidly appeared in the bile in high concentrations as the unchanged compound. Six percent of the dose was excreted after 30 min, and 20% after 90 min. The observed bile-to-plasma concentration ratio of chlorothiazide was 6.1-7.2; after correction for the degree of plasma binding of the drug (91 %), the ratio was 68-80. When the dose of drug was increased 10-fold, with a resultant 6-fold increase in plasma level, the proportion of the dose excreted in 90 min declined about 2-fold, suggesting that the excretion process is saturable. The biliary excretion of chlorothiazide was markedly depressed by the carboxylic acid prcbenecid. Moreover, chlorothiazide strongly depressed the excretion of p-acetylaminohippurate, a carboxylic acid known to be actively secreted into bile. Thus, although chlorothiazide contains neither the carboxyl nor sulfonic acid groups, it appears to be actively secreted into bile by the same process that secretes many carboxylic and sulfonic acids. It was noted in these experiments that chlorothiazide has choleretic activity.