Application of in vitro systems to the prediction of in vivo biokinetics

The kinetics of xenobiotics in biological systems are a critical factor in determining the site and degree of toxicological responses observed. Historically, whole animal kinetic studies coupled with classical compartmental analysis have been used to describe the movement of xenobiotics in biological systems. Often, this traditional approach has not been adequate to meet the needs of toxicologists. In the last few years, biologically based kinetic (BBK) modelling has made a significant contribution to solving this problem. The issue arises as to how in vitro approaches can contribute to this effort. In the past, in vitro models have been used mainly for metabolism studies. Generally, these applications have been qualitative studies to: (1) identify metabolites; (2) investigate metabolic pathways; or (3) assist in interspecies extrapolation 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 predictive models. The current status of BBK modelling and the potential use of in vitro data is discussed with examples of current approaches from the areas of determination of surrogate dose, membrane transport and protein binding.