Physiologically based pharmacokinetic modeling: Principles and applications

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 in- creasing dose. The area under the plasma concentration-time curve (AUCs,) 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 pg/ml. Plasma concentrations were determined at time zero after intravenous administration and after a second dose adminis- tered 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. Keyphrases 0 Bromophenol blue-in rat urine, plasma, and bile, dose-dependent pharmacokinetics, biliary excretion 0 Pharmacoki- netics-bromophenol blue, rat plasma, urine, and bile, biliary excretion I I Biliary excretion-bromophenol blue, rat urine, plasma, and bile, dose-dependent pharmacokinetics Bromophenol blue (I) is a high molecular weight anionic sulfonephthalein dye (670 g/mole, pK, 4.0). Several re- ports (1-3) have shown that I is extensively excreted in the bile and is not metabolized in a variety of species including the rat. Takada et al. (4, 5 ) conducted studies aimed at char- acterizing the role of the intracellular protein fractions Y and Z in the uptake and transport of I in rat hepatocytes, and also developed a linear pharmacokinetic model for the biliary excretion of I after intravenous administration in rats (6). The model adequately described a single low-dose plasma and bile profile, but could not describe the ob- served nonlinearity a t higher doses. The overall aim of these authors was to evaluate I as a model organic anionic compound by characterizing the pharmacokinetics at three different doses. Their report did not fully characterize the pharmacokinetics at any dose. Liver concentrations and plasma protein binding were not measured, and the ob- served nonlinearity was not addressed. Studies on the pharmacokinetics of drugs excreted in the bile have increased in recent years as investigators have become more interested in the effects of liver disease on drug clearance, the effects of first-pass liver clearance on drug bioavailability, the effects of enterohepatic recircu- lation on drug disposition, and the nonlinear excretion of drugs (7-11). Usually these studies have not considered the extent of protein binding, liver-to-plasma and bile- to-liver drug concentration ratios, hepatic blood flow, and bile flow. These factors contribute to the interpretation of hepatobiliary elimination. In addition, the interpreta- tion has been complicated by the use of compounds such as sulfobromophthalein that undergo metabolism. Ideally, a model compound used in studying hepatobiliary elimi- nation would not undergo metabolism, nor enterohepatic recirculation, and would not be pharmacologically ac- tive. The organic anion, bromophenol blue (I), possesses these qualities (2, 4). Therefore, the present investigation was undertaken to: (a ) determine the pharmacokinetic profile 0022-3549/83/ 1000-1 127$01.00/0 @ 1983, American Pharmaceutical Association Journal of Pharmaceutical Sciences I 1127 Vol. 72, No. 10. October 1983