PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING OF PYRENE IN THE RAT

The objective of the present study was to develop a physiologically-ba sed model to simulate the oral and i.v. pharmacokinetics of pyrene in the rat. The physiologically-based pharmacokinetic (PBPK) model for py rene consisted of the following tissue compartments: liver, lungs, adi pose tissue, slowly perfused tissues, and richly perfused tissues inte rconnected with arterial and venous blood pools. The tissue:blood part ition coefficients required for the pyrene PBPK model were estimated b y equilibrium dialysis. Using perfusion-limited descriptions for tissu e uptake and previously determined in vitro-derived hepatic metabolism rate constants (V-max and K-m), the PBPK model predicted a faster cle arance of pyrene than that suggested by the experimental data. The bio logical 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 simu lations could be matched with the experimental data on tissue concentr ations of pyrene only with the considerations of (i) diffusion-limited uptake in slowly perfused tissues and adipose tissue, and (ii) bindin g to proteins in metabolizing tissues (lungs and liver). The present s tudy successfully integrated the available data on oral and i.v, pharm acokinetics of pyrene using a physiological model framework, and ident ified several mechanistic data gaps that should be addressed by future research efforts. (C) 1998 Elsevier Science B.V. All rights reserved.