title: Extrapolation of in vitro enzyme induction data to humans in vivo.
abstract: Enzyme induction generally increases the rate and extent of xenobiotic metabolism in vitro, but physiological constraints can dampen these effects in vivo. Biotransformation kinetics determined in hepatocytes in vitro can be extrapolated to whole animals based on the hepatocellularity of the liver, since the initial velocity of an enzyme-catalyzed reaction is directly proportional to the total enzyme present in the cell. The biotransformation kinetics of various xenobiotics determined with isolated hepatocytes in vitro have been shown to accurately predict pharmacokinetics in whole animals. Analysis of the kinetic data, using physiologically based pharmacokinetics, allows extrapolation of xenobiotic biotransformation across dose routes and species in a biologically realistic context. Several fold variations were observed in the bioactivation of the hepatotoxicant furan by isolated human hepatocytes, due to induction of cytochrome P450 2E1. Extrapolation of these data to humans in vivo showed that furan bioactivation was limited by hepatic blood flow delivery of the substrate. One important consequence of hepatic blood flow limitation is that the amount of metabolite formed in the liver is unaffected by increases in Vmax due to enzyme induction. Therefore, interindividual variations in cytochrome P450 2E1 among human populations would not affect the bioactivation of many rapidly metabolized hazardous chemical air pollutants. The hepatic blood flow limitation of biotransformation is also observed after oral bolus dosing of rapidly metabolized compounds. More slowly metabolized xenobiotics, such as therapeutic agents, are only partially limited by hepatic blood flow and other processes.
authors.affiliation: Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709-2137, USA. kedderis@ciit.org
authors.forename: G L
authors.initials: GL
authors.lastname: Kedderis
mesh_terms: D000818:Animals; D001711:Biotransformation; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis*; D004790:Enzyme Induction; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008954:Models, Biological; D015262:Xenobiotics / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D015262:Xenobiotics; D019392:Cytochrome P-450 CYP2E1