Calibration and validation of a physiologically based model for soman intoxication in the rat, marmoset, guinea pig and pig

Journal of Applied Toxicology - Tập 32 Số 9 - Trang 673-686 - 2012
Kaizhen Chen1, Kok‐Yong Seng1,2
1Bioengineering Laboratory, Defence Medical and Environmental Research Institute, DSO National Laboratories, 27 Medical Drive, Singapore, 117510 Republic of Singapore
2Kok-Yong Seng, Bioengineering Laboratory, Defence Medical and Environmental Research Institute, DSO National Laboratories, 27 Medical Drive, Singapore 117510, Republic of Singapore.

Tóm tắt

ABSTRACTA physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model has been developed for low, medium and high levels of soman intoxication in the rat, marmoset, guinea pig and pig. The primary objective of this model was to describe the pharmacokinetics of soman after intravenous, intramuscular and subcutaneous administration in the rat, marmoset, guinea pig, and pig as well as its subsequent pharmacodynamic effects on blood acetylcholinesterase (AChE) levels, relating dosimetry to physiological response. The reactions modelled in each physiologically realistic compartment are: (1) partitioning of C(±)P(±) soman from the blood into the tissue; (2) inhibition of AChE and carboxylesterase (CaE) by soman; (3) elimination of soman by enzymatic hydrolysis; (4) de novo synthesis and degradation of AChE and CaE; and (5) aging of AChE–soman and CaE–soman complexes. The model was first calibrated for the rat, then extrapolated for validation in the marmoset, guinea pig and pig. Adequate fits to experimental data on the time course of soman pharmacokinetics and AChE inhibition were achieved in the mammalian models. In conclusion, the present model adequately predicts the dose–response relationship resulting from soman intoxication and can potentially be applied to predict soman pharmacokinetics and pharmacodynamics in other species, including human. Copyright © 2011 John Wiley & Sons, Ltd.

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Journal of Applied Toxicology

Tập 32 Số 9

673-686

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