Modeling cyanide release from nitriles: prediction of cytochrome P450 mediated acute nitrile toxicity.

A mechanism-based model for prediction of acute nitrile toxicity was developed using octanol-water partition coefficients (log P) and estimated rates of alpha-hydrogen atom abstraction as variables. Relative rates of hydrogen atom abstraction were derived from differences in heats of formation for ground-state and radical geometries and radical ionization potentials. Calculated energies of activation for all potential sites of oxidation for a given nitrile were used to estimate partitioning of metabolites among multiple oxidative pathways. logP and the resulting corrected rate constants for alpha-carbon oxidation were effective variables in an acute toxicity model of structurally diverse nitriles. The pharmacokinetics of substrate disposition is discussed in the context of multiple metabolic pathways. Structure-toxicity relationships are also discussed.