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OXIDATIVE AND HYDROLYTIC METABOLISM OF TYPE I PYRETHROIDS IN RAT AND HUMAN HEPATIC MICROSOMES
Citation:
SCOLLON, E., J. M. STARR, M. F. HUGHES, AND M. J. DEVITO. OXIDATIVE AND HYDROLYTIC METABOLISM OF TYPE I PYRETHROIDS IN RAT AND HUMAN HEPATIC MICROSOMES. Presented at ISSX National Meeting, Rio Grande, PUERTO RICO, October 22 - 26, 2006.
Description:
Pyrethroids are a class of neurotoxic insecticides used in a variety of agricultural and household activities. Increased potential for human exposure to pyrethroids has prompted pharmacokinetic research. To that end, our laboratory has determined the in vitro clearance of the Type I pyrethroids permethrin, bifenthrin, resmethrin and bioallethrin in male rat and human hepatic microsomes. The aim of this study was to determine the clearance due to NADPH-dependent oxidative metabolism and NADPH-independent hydrolytic metabolism. 0.5 µM solutions of cis-permethrin, trans-permethrin, permethrin (40 cis: 60 trans), bifenthrin, and resmethrin were incubated in hepatic microsomes in the presence or absence of NADPH. Metabolism was measured using a parent depletion approach. Parent compound concentrations were determined by LC/MS. The primary mechanism for clearance in rat and human hepatic microsomes was NADPH-dependent. Bioallethrin, cis-permethrin, bifenthrin were solely metabolized by oxidative mechanisms. Clearance values (rate±SD) ranged between 225±21 (bifenthrin) and 1219±107 mL/min/kg BW (bioallethrin) in the rat and between 20±7 (bifenthrin) and 74±5 mL/min/kg BW (bioallethrin) in the human. In contrast, significant esterase activity contributed to the clearance of resmethrin and trans-permethrin in the rat (46% and 65%) and human (100% and 41%). The rank order for total clearance (oxidative and hydrolytic) was bioallethrin > cis-permethrin > trans-permethrin > resmethrin > bifenthrin in the rat and trans-permethrin > resmethrin > bioallethrin > cis permethrin > bifenthrin in human hepatic microsomes. The clearance rates of cis and trans-permethrin were largely unaffected by combining them in a mixture in the rat microsomes. However, in human microsomes, clearance of cis and trans-permethrin decreased 57% and 36% compared to single isomer clearance rates. The decrease may be an indication of competitive inhibition. Overall, the in vitro metabolism of selected Type I pyrethroids varies by pathway and rate. This study demonstrates the variability associated with pyrethroid metabolism and the uncertainties involved with extrapolating from rodent to human using default methodologies. (This abstract does not reflect US EPA policy.)