Compartmental analysis of the disposition of benzo[a]pyrene in rats

We have previously reported the disposition of Benzo[a]pyrene (B[a]P) and its metabolites in male Sprague-Dawley rats following intratracheal instillation of [3H]B[a]P [Weyand, E.H. and Bevan, D.R. (1986) Cancer Res, 46, 5655–5661]. In some experiments, cannulas were implanted in the bile duct of the animals prior to administration of [3H]B[a]P [Weyand, E.H. and Bevan, D.R. (1987) Drug Metab. Disposition, 15, 442–448]. Based on these data, we have developed a compartmental model of the distribution of radioactivity to provide a quantitative description of the fate of B[a]P and its metabolites in rats. Modeling of the distribution of radioactivity was performed using the Simulation, Analysis and Modeling (SAAM)and conversational SAAM(CONSAM) computer programs. Compartments in the model included organs into which the largest amounts of radioactivity were distributed as well as pathways for excretion of radioactivity from the animals. Data from animals with and without cannulas implanted in the bile duct were considered simultaneously during modeling. Radioactivity was so rapidly absorbed from the lungs that an absorption phase into blood was not apparent at the earliest sampling times. Using the model of extrapolate to shorter times, it was predicted that the maximum amount of radioactivity was present in blood within 2 min after administration. In addition, considerable recycling of radioactivity back to lungs from blood was predicted by the model. Transfer of radioactivity from blood to liver and carcass (skin, muscle, bones, fat and associated blood) also was extensive. Carcass was modeled as the sum of two compartments to obtain agreement between the model and experimental data. The model accounted for enterohepatic circulation of B[a]P metabolites; data also required that intestinal secretion be included in the model. Quantitative data obtained from compartmental analysis included rate constants for transfer of radioactivity among compartments as well as statistical parameters indicating the identifiability of the rate constants. That the model is consistent with two sets of data, those obtained in animals with and without a biliary cannula, indicates its potential utility in predicting the disposition of B[a]P and its metabolites in vivo.