RELEVANCE OF IN-VITRO KINETIC-PARAMETERS TO IN-VIVO METABOLISM OF XENOBIOTICS

Numerous in vitro systems are available for the study of pathways and kinetics of drug metabolism and the question is often posed of their u tility as predictors of in vivo disposition behaviour. Of particular i nterest is the feasibility of predicting in vivo metabolic clearance o f 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 cl earance. The cornerstone of this procedure is the parameter intrinsic clearance which may be defined biochemically as the V-max/K-m ratio. E xtrapolation from the in vitro data requires scaling factors from eith er microsomal protein recovery, cellularity and/or organ weight and th e use of a liver model (e.g. well-stirred liver) to express the kineti c data in terms of circulating drug concentrations (blood or plasma) r ather than concentration at the enzyme site. The feasibility of this s trategy and the relative merits of using hepatic microsomal and hepato cyte data will be discussed using a body of information on 25 drugs.