PREDICTION OF ANTICHOLINESTERASE ACTIVITY AND URINARY METABOLITES OF ISOFENPHOS - USE OF A PERCUTANEOUS PHYSIOLOGICALLY-BASED PHARMACOKINETIC PHYSIOLOGICALLY-BASED PHARMACODYNAMIC MODEL

An isofenphos percutaneous PBPK/PBPD model was developed to predict metabolite concentrations in tissues and the inhibition of tissue esterases. Rat V-max and K-m values for the metabolism of isofenphos to des N-isopropyl isofenphos, isofenphos-oxon, and des N-isopropyl isofenphos oxon (DNIO) by liver microsomal P-450 enzymes were used in the PBPK portion of the model along with estimated partition coefficients for isofenphos and metabolites between liver, fat, brain, kidney, skin, vessel rich group, vessel poor group, and blood. In the PBPD portion of the model, the bimolecular rate constants for the phosphorylation of brain and blood acetylcholinesterase (AChE), and liver, blood, and brain carboxylesterases and butyrylcholinesterases by DNIO were used to predict their inhibition. Model mass balance data provided summary information on the relationship between topically applied isofenphos and exposure biomarkers such as urinary monoethylphosphate, 2-hydroxy hippuric acid, and inhibited blood enzymes.