Continuous system modeling of equilibrium dialysis for determinations of tissue partitioning of parathion and paraoxon

Abstract

A tissue/blood partition coefficient, defined as the ratio of tissue chemical concentration to that of the venous outflow of the tissue when at equilibrium, is an important parameter required for physiological based pharmacokinetic models. While many techniques have been developed to quantify tissue/blood partition coefficients for various chemicals, there is no single best approach for their determination. In the current study, equilibrium dialysis of the organophosphorus insecticide parathion and its active metabolite paraoxon was undertaken to assess their partitioning into rat liver. A mass balance analysis of the contents of the dialysis cells suggested that significant levels of parathion and paraoxon were bound to the dialysis membranes. There was no evidence of metabolism of either parathion or paraoxon by the very dilute liver homogenate utilized in the dialysis. In order to investigate the potential impact of binding of a chemical to dialysis membrane during determination of partition coefficients, a computer model of a dialysis system was constructed. The model assumed that all processes occurring within the dialysis cell were first or second order in nature, and that binding to the dialysis membrane occurred symmetrically on both sides of the membrane. Variations in the total number of simulated binding sites on dialysis membrane revealed that increasing the degree of membrane binding resulted in decreased compound on the homogenate and buffer sides of the dialysis cells. However, the final tissue/buffer partition coefficient was unaffected by these alterations in membrane binding, although increased membrane binding prolonged the incubation time required to achieve equilibrium. These simulations suggest that loss of a compound to membrane binding does not preclude the use of equilibrium dialysis for determination of tissue/buffer, and therefore tissue/blood, partition coefficients, provided the dialysis system is allowed to proceed to equilibrium. © 2002 Published by Elsevier Science Ireland Ltd.