A physiologically based pharmacokinetic (PB/PK) model for multiple exposure routes of soman in multiple species

Abstract

A physiologically based pharmacokinetic (PB/PK) model has been developed in advanced computer simulation language (ACSL) to describe blood and tissue concentration-time profiles of the C(+/-)P(-) stereoisomers of soman after inhalation, subcutaneous and intravenous exposures at low (0.8-1.0 x LD(50)), medium (2-3 x LD(50)) and high (6 x LD(50)) levels of soman challenge in three species (rat, guinea pig, marmoset). Allometric formulae were used to compute the compartment volumes, blood flow rates, tidal volume and respiratory rate based upon total animal weight. Blood/tissue partition coefficients for soman, initial carboxylesterase and acetylcholinesterase levels and the rate constants for interactions between soman and these enzymes were species-dependent and were obtained from in vitro measurements reported in the literature. The model incorporated arterial and venous blood, lung, kidney, liver, richly perfused, poorly perfused and fat tissue compartments as well as subcutaneous and nasal exposure site compartments. First-order absorption from linearly filled soman deposits into metabolizing exposure site compartments was employed to model subcutaneous and inhalation exposures. The model was validated by comparing the predicted and observed values for C(+/-)P(-)-soman in arterial blood at various times following exposure and by regression analysis. Sensitivity analysis was used to determine the effects of perturbations in the model parameters on the time-course of arterial C(-)P(-)-soman concentrations for different exposure routes. In our evaluation of 28 datasets, predicted values were generally within 95% confidence limits of the observed values, and regression coefficients comparing predicted and observed data were greater than 0.85 for 95% of the intravenous and subcutaneous datasets and 25% of the inhalation datasets. We conclude that the model predicts the soman toxicokinetics for doses >or=1 x LD(50) for intravenous and subcutaneous exposures and inhalation exposures of 8 min or less sufficiently well to allow its use in the modeling of bioscavenger protection.