Comparison of in vivo derived and scaled in vitro metabolic rate constants for several volatile organic compounds (VOCs)

• Published in: Toxicology in vitro Vol. 69; p. 105002
• Main Authors: Kenyon, Elaina M., Eklund, Christopher, Pegram, Rex A., Lipscomb, John C.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2020; Elsevier Science Ltd
• Subjects: Allyl Compounds - pharmacokinetics; Animals; Binding; Biotransformation; Bromodichloromethane; Chemicals; Data collection; Hydrocarbons, Chlorinated - pharmacokinetics; in vitro to in vivo extrapolation; In vivo methods and tests; IVIVE; Laboratory animals; Male; Metabolic Clearance Rate; Metabolic rate; Metabolic rate parameters; Metabolism; Models, Biological; Organic compounds; Parameter estimation; PBPK; Physiologically based pharmacokinetic modeling; Propane - analogs & derivatives; Propane - pharmacokinetics; Rate constants; Rats, Inbred F344; VOCs; Volatile organic compounds; Volatile Organic Compounds - pharmacokinetics; Volatile organic compounds; Physiologically based pharmacokinetic modeling; Biotransformation; IVIVE; Metabolic rate parameters; in vitro to in vivo extrapolation; PBPK
• ISSN: 0887-2333; 1879-3177; 1879-3177
• DOI: 10.1016/j.tiv.2020.105002

Metabolic rate parameters estimation using in vitro data is necessary due to numbers of chemicals for which data are needed, trend towards minimizing laboratory animal use, and limited opportunity to collect data in human subjects. We evaluated how well metabolic rate parameters derived from in vitro data predict overall in vivo metabolism for a set of environmental chemicals for which well validated and established methods exist. We compared values of VmaxC derived from in vivo vapor uptake studies with estimates of VmaxC scaled up from in vitro hepatic microsomal metabolism studies for VOCs for which data were available in male F344 rats. For 6 of 7 VOCs, differences between the in vivo and scaled up in vitro VmaxC estimates were less than 2.6-fold. For bromodichloromethane (BDCM), the in vivo derived VmaxC was approximately 4.4-fold higher than the in vitro derived and scaled up VmaxC. The more rapid rate of BDCM metabolism estimated based in vivo studies suggests other factors such as extrahepatic metabolism, binding or other non-specific losses making a significant contribution to overall clearance. Systematic and reliable utilization of scaled up in vitro biotransformation rate parameters in PBPK models will require development of methods to predict cases in which extrahepatic metabolism and binding as well as other factors are likely to be significant contributors. •Evaluated if metabolic rate parameters derived from in vitro data predict in vivo metabolism for set of volatile chemicals•For most chemicals differences between scaled in vitro and in vivo biotransformation rates were less than 2.6-fol•Methods are needed to predict when other physiological processes significantly contribute to metabolic clearance