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

Autor: Sweeney, R.E., Langenberg, J.P., Maxwell, D.M.
Přispěvatelé: TNO Defensie en Veiligheid
Rok vydání: 2006
Předmět:
Male
Soman
Chemical warfare agents
Toxicology
Partition coefficient
Animal tissue
Carboxylesterase
Tidal volume
Cavia porcellus
Provocation test
Priority journal
Acetylcholinesterase
9000-81-1
Stereoisomerism
Callithrix
Computer simulation
Toxicokinetics
Venous blood
Injections
Intravenous
Acetylcholinesterase
Lung perfusion
Computer language
Sensitivity analysis
Regression analysis
BLood level
Soman
96-64-0
Carboxylesterase
59536-71-9
83380-83-0
9016-18-6
9028-01-7
Blood flow velocity
Injections
Subcutaneous
Guinea Pigs
Adipose tissue
Breathing rate
Models
Biological
Exposure
Tissue level
Administration
Inhalation
Animals
Animalia
Kidney perfusion
Animal experiment
Rats
Wistar
Allometry
LD 50
Arterial blood
In vitro study
Cholinesterase inhibitors
Body weight
Guinea pig
Nonhuman
Marmoset
Rats
Liver perfusion
Metabolism
Enzyme
Rat
Marmosets
Controlled study
Zdroj: Archives of Toxicology, 80, 719-731
Popis: 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 × LD50), medium (2-3 × LD50) and high (6 × LD50) 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 ≥1 × LD50 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. © 2006 Springer-Verlag.
Databáze: OpenAIRE
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