Physiologically-based pharmacokinetic modeling of pyrene in the rat

The objective of the present study was to develop a physiologically-based model to simulate the oral and i.v. pharmacokinetics of pyrene in the rat. The physiologically-based pharmacokinetic (PBPK) model for pyrene consisted of the following tissue compartments: liver, lungs, adipose tissue, slowly perfused tissues, and richly perfused tissues interconnected with arterial and venous blood pools. The tissue:blood partition coefficients required for the pyrene PBPK model were estimated by equilibrium dialysis. Using perfusion-limited descriptions for tissue uptake and previously determined in vitro-derived hepatic metabolism rate constants (V(max) and K(m)), the PBPK model predicted a faster clearance of pyrene than that suggested by the experimental data. The biological basis of PBPK model then provided an opportunity to refine the estimate of V(max), and to explore and uncover additional mechanistic determinants of pyrene disposition in vivo. Accordingly, the in vitro V(max) had to be lowered by about a factor of 10 to adequately simulate experimental data on pyrene pharmacokinetics. Further, the model simulations could be matched with the experimental data on tissue concentrations of pyrene only with the considerations of (i) diffusion-limited uptake in slowly perfused tissues and adipose tissue, and (ii) binding to proteins in metabolizing tissues (lungs and liver). The present study successfully integrated the available data on oral and i.v. pharmacokinetics of pyrene using a physiological model framework, and identified several mechanistic data gaps that should be addressed by future research efforts.