Relevance of in vitro kinetic parameters to in vivo metabolism of xenobiotics

Toxicol In Vitro. 1994 Aug;8(4):507-12. doi: 10.1016/0887-2333(94)90002-7.


Numerous in vitro systems are available for the study of pathways and kinetics of drug metabolism and the question is often posed of their utility as predictors of in vivo disposition behaviour. Of particular interest is the feasibility of predicting in vivo metabolic clearance of noxious chemicals in humans from data obtained in vitro using human tissue/gene expression systems. In theory the easily defined in vitro parameters V(max) and K(m) can be scaled to provide in vivo metabolic clearance. The cornerstone of this procedure is the parameter intrinsic clearance which may be defined biochemically as the V(max)/K(m) ratio. Extrapolation from the in vitro data requires scaling factors from either microsomal protein recovery, cellularity and/or organ weight and the use of a liver model (e.g. well-stirred liver) to express the kinetic data in terms of circulating drug concentrations (blood or plasma) rather than concentration at the enzyme site. The feasibility of this strategy and the relative merits of using hepatic microsomal and hepatocyte data will be discussed using a body of information on 25 drugs.