Dose-Dependent Pharmacokinetics and Hepatobiliary Transport of Bromophenol Blue in the Beagle

Abstract

The pharmacokinetic profile of bromophenol blue (I) in the plasma, urine, and bile of beagle dogs was determined after intravenous administration of 5-, 20-, and 30-mg/kg doses. In addition, two competitors, probenecid and phenylbutazone, were interacted with I in vivo and with I and rat liver cytoplasmic protein fractions Y and Z in vitro as a means of elucidating the mechanism of intrahepatic transport of I. Compound I was determined spectrophotometrically at 587nm. In plasma, I displayed apparent first-order dose-dependent kinetics. The percentage of I bound to plasma proteins was ~92.5% over the dose range studied. Consecutive injections of equal doses of I produced statistically different terminal half-lives (p < 0.05), suggesting the possibility of a saturable uptake process. In the presence of each competitor, the disposition of I was altered significantly (p < 0.05): phenylbutazone displaced I from plasma protein, while probenecid decreased the binding of 1 to liver proteins in the Z-fraction. The Z-fraction bound a larger amount of 1 than the Y-fraction, suggesting a larger binding capacity. Under no circumstances was the binding of I to the Y-fraction altered. Cumulative biliary excretion data showed that the elimination of I in bile accounted for 92–99% of the dose delivered. The biliary excretion σ− plots displayed no dose dependency, suggesting that the dose-dependent plasma half-life is due to a dose-dependent liver uptake (as opposed to elimination) process.