ABSORPTION AND DISPOSITION OF CHLOROTHIAZIDE IN RATS (CAFFEINE

The pharmacokinetics of chlorothiazide in five rats after intravenous administration was studied; the drug is almost completely excreted unchanged in urine (92% in 25 hr) with a terminal half-life of 76.4 min and a total plasma clearance of 20.6 ml/min/kg. Studies on the interspecies clearance correlations for 22 drugs (chlorothiazide, 6 (beta)-lactam antibiotics and 15 other acidic and basic drugs) showed that the unbound plasma clearance of these drugs are generally species independent if based on unit BSA which suggests that the unbound clearance is potentially useful in predicting unbound clearance in animal scale-up studies. The mean urinary recovery of chlorothiazide in 6 rats fell from 57% to 15% as oral doses increased from 0.93 mg/kg to 70.2 mg/kg. The degree of dose-dependency in absorption was almost identical in rats and humans when doses were based on mg/m('2) BSA which suggests that absorptive capacity/unit BSA may be similar among different species. The drug was found not to decompose in the GI tract and to be absorbed from all segments of the GI tract with relative absorption rate of duodenum, jejunum > large intestine, ileum and stomach. The absorption of chlorothiazide could be saturable, might not be affected by the pH of the solution or limited by permeability. The limited solubility could be ruled out as a contributing factor for the incomplete absorption at doses below 2.55 mg/kg in rats and 125 mg in humans. Prolonged drug absorption, probably taking place in the large intestine in humans and rats, was proposed to account for the significant 24-48hr urinary recoveries of the drug.;The apparent aqueous solubility of chlorothiazide at room temperature increased linearly from 225 mg/ml to 533 mg/ml with increasing concentration of caffeine probably due to the formation of chlorothiazide-caffeine complex. The oral absorption of chlorothiazide in 13 rats at 28.3 mg/kg was enhanced (51%) by coadministration of 20 mg of caffeine. This was attributed to the formation of the complex which reduced the degree of chlorothiazide precipitation and increased the dissolution rate of the precipitated drug in the GI tract. The increase of the in situ absorption rate of chlorothiazide by caffeine was attributed to the effect of caffeine on the increase of local blood flow at absorption site and systemic mesenteric blood flow.