Dose-Dependent Pharmacokinetics and Biliary Excretion of Bromophenol Blue in the Rat

Abstract

□ Concentrations of bromophenol blue (I) in plasma, urine, and bile were determined spectrophotometrically after intravenous bolus injections and infusions in rats. The plasma concentrations were found to decrease monoexponentially after all doses except the highest, where the decrease was biexponential. Although the disposition kinetics of I were apparently first-order at all doses, the half-life increased with increasing dose. The area under the plasma concentration–time curve (AUC0-∞) increased disproportionately with increasing dose. The binding of I to rat plasma proteins, as determined by equilibrium dialysis, showed that the fraction bound (96%) remained constant in the concentration range of 10-300 μg/ml. Plasma concentrations were determined at time zero after intravenous administration and after a second dose administered 20 min later when plasma concentrations from the first dose were minimal. The apparent first-order elimination rate constant for the plasma concentration decline following the second dose was significantly less than after the first dose, indicating that the residual dye in the liver altered the elimination of I after the second dose. The fraction of the dose in the liver decreased with increasing dose, indicating a saturable uptake process. The biliary excretion profile reflected the uptake saturation that occurred in the liver and demonstrated that the biliary excretion of I depended on the amount present in the liver. When liver damage was induced by exposure to carbon tetrachloride, dye concentrations in the plasma, liver, and kidney increased markedly.