Poster: ADME AOP Framework

A Workflow to Investigate Exposure and Pharmacokinetics Influences on High-Throughput in vitro Chemical Screening Based on Adverse Outcome Pathways
Jeremy A. Leonard: ADME AOP Framework
PRESENTING AUTHOR: 

Jeremy A. Leonard, Post-Doctoral Grantee

INSTITUTION / COMPANY : 

US Environmental Protection Agency

ABSTRACT CONTENT / DETAILS: 

Adverse outcome pathways (AOPs) link known population outcomes to a molecular initiating event (MIE) that can be quantified using high-throughput in vitro methods. Despite the conceptual clarity proffered by the AOP framework, practical application of AOPs in chemical - specific risk assessment requires consideration of exposure and absorption, distribution, metabolism, excretion (ADME) properties of chemicals.

We developed a conceptual workflow to consider exposure and ADME properties in relationship to a MIE and demonstrated the utility of this workflow using a previously established AOP, acetylcholinesterase (AChE) inhibition.

Thirty active chemicals found to inhibit AChE in the ToxCast (TM) assay were examined with respect to their exposure and absorption potentials, and their ability to cross the blood - brain barrier (BBB).

Structural similarities of active compounds were compared against structures of in active compounds to detect possible non-active parents that might have active metabolites. Application of the workflow resulted in ten “low priority” chemicals out of the thirty original active compounds. Fifty two of the 1,029 inactive compounds exhibited a similarity threshold above 75% with their nearest active neighbors.

Excluding compounds that may not be absorbed, 22 could be potentially toxic following metabolism.

The incorporation of exposure and ADME properties into the conceptual workflow resulted in prioritization of 20 out of 30 active compounds identified in an AChE inhibition assay for further analysis and identification of several inactive parent compounds of active metabolites. This qualitative approach can minimize cost and time by eliminating compounds that may have otherwise undergone additional analyses.