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COMPARISON OF IN VIVO DERIVED AND SCALED IN VITRO METABOLIC RATE CONSTANTS FOR SOME VOLATILE ORGANIC COMPOUNDS (VOCS)
Citation:
KENYON, E. M., R. A. PEGRAM, C. R. EKLUND, AND J. C. LIPSCOMB. COMPARISON OF IN VIVO DERIVED AND SCALED IN VITRO METABOLIC RATE CONSTANTS FOR SOME VOLATILE ORGANIC COMPOUNDS (VOCS). Presented at Society of Toxicology (SOT) Annual Meeting, San Francisco, CA, March 11 - 15, 2012.
Impact/Purpose:
Systematic and reliable utilization of scaled up metabolic rate parameters from in vitro studies in PBPK models will require evaluation and testing of the assumptions and scaling factors used in these calculations and development of methods to predict when extra hepatic metabolism is likely to be significant.
Description:
The reliability of physiologically based pharmacokinetic (PBPK) models is directly related to the accuracy of the metabolic rate parameters used as model inputs. When metabolic rate parameters derived from in vivo experiments are unavailable, they can be estimated from in vitro data. In vitro data are scaled up for use in PBPK models on the basis of mg of microsomal protein per gram of liver, liver weight and body weight. 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 four VOCs for which data were available in male F344 rats. For two of the four VOCs, agreement between the in vivo and scaled up VmaxC estimates differed by less than less than 2-fold; for l,l-dichloropropene the in vivo vapor uptake VmaxC and scaled up in vitro VmaxC were 5.76 and 7.22 mg/hr-kg, respectively and for 1,2-dichloroethane the corresponding VmaxC were 3.25 and 5.5 mg/hr-kg. For bromodichloromethane (BDCM), the in vivo derived VmaxC was approximately 5-fold higher than the in vitro derived and scaled up VmaxC (12.8 vs. 2.65 mg/hr-kg). In the case of 2,2-dichloropropane, (2,2-DCP) which was essentially unmetabolized in vitro by hepatic microsomes or cytosol, and relatively slowly metabolized in in vivo vapor uptake studies (compared to 1,1-dichloropropene), the available data did not permit a direct comparison of VmaxC. The more rapid rate of metabolism estimated on the basis of in vivo studies for BDCM and 2,2-DCP suggest the possibility of extra hepatic metabolism making a significant contribution to overall clearance. Systematic and reliable utilization of scaled up metabolic rate parameters from in vitro studies in PBPK models will require evaluation and testing of the assumptions and scaling factors used in these calculations and development of methods to predict cases in which extrahepatic metabolism is likely to be a significant contributor. (This abstract does not necessarily reflect Agency policy).