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Gender and Species-Mediated Differences in the In Vitro Metabolism of Triadimefon by Rodent Hepatic Microsomes
Citation:
Ritger, S., J. F. KENNEKE, C. S. MAZUR, W. M. HENDERSON, AND J. Fisher. Gender and Species-Mediated Differences in the In Vitro Metabolism of Triadimefon by Rodent Hepatic Microsomes. Presented at Society of Toxicology Annual Meeting, Seattle, WA, March 16 - 20, 2008.
Impact/Purpose:
This task is designed to respond to a high-priority ORD research initiative titled “Computational Toxicology”, which will enable EPA Program Offices and other regulators to prioritize toxicity-testing requirements for regulated chemicals. The overall success of the initiative is dependent on the development and merging of new computational and genomic tools.
Description:
Understanding how metabolism kinetics differ between genders and species is important in developing informative pharmacokinetic models and accurately assessing risk. Metabolism of the conazole fungicide Triadimefon (TDN) was studied in hepatic microsomes of SD rats and CD-1 mice. Michaelis-Menten saturation kinetic parameters were calculated using both substrate depletion and product formation reaction velocities. For values calculated from substrate depletion data, male rat microsomes were found to metabolize TDN most rapidly. Differences in stereoselectivity of TDN metabolism were also addressed by measuring changes in the enantiomeric ratio with respect to time. These data indicate a need to further investigate differences in metabolic kinetics and mechanisms between species and genders of model organisms in order to develop more accurate pharmacokinetic models for risk assessment.