Science Inventory

Chiral Pesticide Pharmacokinetics: A Range of Values


Kenneke, J., S. Marchitti, S. Rawat, D. Chang, Chris Grulke, Chris Mazur, AND Rocky Goldsmith. Chiral Pesticide Pharmacokinetics: A Range of Values. Presented at Society of Toxicology Meeting, San Antonio, TX, March 10 - 14, 2013.


The poster was presented at Society of Toxicology National Meeting. March 10-14, 2013. San Antonio, TX


Approximately 30% of pesticides are chiral and used as mixtures of two or more stereoisomers. In biological systems, these stereoisomers can exhibit significantly different pharmacokinetics (absorption, distribution, metabolism, and elimination). In spite of these differences, these “mixtures” are often treated as a single compound in exposure and hazard assessment. To evaluate the impact of pharmacokinetic differences on internal exposure (dose) estimates, we studied the stereoisomer-specific metabolism of twenty chiral 1,2,4-triazole fungicides in hepatic microsomes, hepatocytes, and purified cytochrome P450s (P450). Additionally, we measured the metabolism of the pure stereoisomers for three of the fungicides. Studies indicated that CYP3A4 was a major metabolizing enzyme for a majority of the fungicides. In general, the stereoisomers of each fungicide (pure and in the fungicide mixture) exhibited significantly different clearance rates. With some compounds, one or more stereoisomers inhibited the clearance of the other stereoisomers. Results were consistent across genders. In an effort to explain the observed stereoisomer clearance rates, we utilized a directed ligand-based pharmacophore analysis to identify key ligand features. Triadimefon was the only fungicide that preferentially underwent stereoselective carbonyl reduction rather than P450-mediated oxidation. Reduction of the prochiral carbonyl produced four stereoisomers of triadimenol. Relative formation of the triadimenol stereoisomers varied among 16 vertebrate species; the individual triadimenol stereoisomers differentially inhibited CYP3A4 metabolism. These results suggest that treating a chiral pesticide as a single chemical rather than a mixture could introduce errors in risk assessment. Although this work was reviewed by EPA and approved for publication, it may not necessarily reflect official Agency policy.

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Record Details:

Product Published Date: 03/11/2013
Record Last Revised: 12/17/2013
OMB Category: Other
Record ID: 253990