The modulating effects of endogenous substances on drug metabolising enzymes and implications for inter-individual variability and quantitative prediction.

The cytochrome P450 family of enzymes play an important role in the metabolism of drugs and other xenobiotics. While genotypic variation can contribute to the inter-individual variability in drug metabolism, individuals sharing the same genotype for an enzyme can still show considerable variability in drug metabolising capacity by that enzyme. It is well recognised that in some disease states (e.g. inflammation, infection, diabetes) or other physiological conditions (e.g. pregnancy), the clearance of drugs may significantly alter, possibly via modulation of drug metabolising enzymes by varying levels of endogenous substances. This review investigates the current knowledge on the modulating effects of various endogenous substances on DMEs in vitro and possible utility of available in vitro data for quantitative prediction of clinical outcome. It is postulated that understanding and estimating the inter-individual variability in DMEs within each population might be possible by application of in vitro in vivo extrapolation linked physiologically-based pharmacokinetic modelling. However, in vitro information for building such quantitative relationships is currently not abundant.