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IN VITRO ESTIMATES OF METABOLIC PARAMETERS AND THEIR USE IN PREDICTIVE PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING (PBPK) OF THE TYPE I PYRETHROIDS PERMETHRIN AND BIFENTHRIN
Citation:
Scollon, E. J., M F. Hughes, M J. DeVito, R. TORNERO-VELEZ, AND S. J. Godin. IN VITRO ESTIMATES OF METABOLIC PARAMETERS AND THEIR USE IN PREDICTIVE PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING (PBPK) OF THE TYPE I PYRETHROIDS PERMETHRIN AND BIFENTHRIN. Presented at Society of Toxicology Annual Meeting, New Orleans, LA, March 06 - 10, 2005.
Description:
Pyrethroids are a class of neurotoxic insecticides that are used in a variety of agricultural and household activities. Hepatic clearance of the Type I pyrethroids permethrin and bifenthrin may be a critical determinant of their toxic effect. Rat LD50s reported in the literature for permethrin and bifenthrin are 1200 and 70 mg/kg, respectively. We determined in vitro metabolic parameters in adult male rat liver microsomes for permethrin and bifenthrin using a parent depletion approach. Km (3.82?M ? 0.07 and 5.41?M ? 7.26), Vmax (309.32 ? 66.69 and 206.67 pmoles/min/mg protein ? 86.96) and hepatic CLint (9.7E-3 and 4.59E-3 L/hr/mg protein) were determined for the cis and trans isomers of permethrin, respectively. The in vitro parameters for the metabolism of bifenthrin were: Km = 34.75 ?M ? 41.94; Vmax = 845 pmoles/min ? 479; hepatic CLint = 2.93E-3 L/hr/mg protein. The 3 to 4-fold difference in hepatic clearance rates between the permethrin isomers and bifenthrin do not account for their disparity in toxicity. This suggests that metabolism at other sites as well as pharmacodynamic effects are critical determinants of the toxicity of permethrin and bifenthrin. Hepatic clearance alone does not appear to fully explain the differences in the toxicity between bifenthrin and permethrin. (SJG supported by CT826513. This abstract does not represent US EPA policy.)