APPLICATION OF IN-VITRO SYSTEMS TO THE PREDICTION OF IN-VIVO BIOKINETICS

The kinetics of xenobiotics in biological systems are a critical facto r in determining the site and degree of toxicological responses observ ed. Historically, whole animal kinetic studies coupled with classical compartmental analysis have been used to describe the movement of xeno biotics in biological systems. Often, this traditional approach has no t been adequate to meet the needs of toxicologists. In the last Few ye ars, biologically based kinetic (BBK) modelling has made a significant contribution to solving this problem. The issue arises as to how in v itro approaches can contribute to this effort. In the past, in vitro m odels have been used mainly for metabolism studies. Generally, these a pplications have been qualitative studies to: (1) identify metabolites ; (2) investigate metabolic pathways; or (3) assist in interspecies ex trapolation issues. The quantitative application of in vitro data has been restricted by limitations of experimental models and the lack of a theoretical framework for the incorporation of these data into predi ctive models. The current status of BBK modelling and the potential us e of in vitro data is discussed with examples of current approaches fr om the areas of determination of surrogate dose, membrane transport an d protein binding.