Relevance of desorption kinetics and permeability for in vitro-based predictions of hepatic clearance in fish.

Abstract

The impact of desorption kinetics and permeation kinetics on in vitro-based predictions of in vivo hepatic blood clearances is investigated in the present study. Most commonly, possible limitations due to slow desorption of chemicals from albumin or slow permeation of chemicals through cellular membranes are not considered when in vivo clearances are predicted from in vitro biotransformation rate constants. To evaluate whether the most commonly used extrapolation models might thus overlook important kinetic limitations, we compare predictions of in vivo clearance that explicitly consider desorption and permeation kinetics with predictions of in vivo clearance that neglect these aspects. Our results show that strong limitations due to slow permeation kinetics are possible depending on the assumed permeability value. While permeability values estimated with a mechanistic approach are fast enough to avoid significant limitations, other experimentally derived permeability values lead to dramatically decreased in vivo clearance predictions. These latter values lead to unrealistically low in vivo biotransformation estimates. Furthermore, we also evaluated the implications of desorption kinetics using experimentally determined desorption rate constants. These evaluations show that slow desorption kinetics are unlikely to limit in vivo clearance.