Sensitivity analysis on a physiologically-based pharmacokinetic and pharmacodynamic model for diisopropylfluorophosphate-induced toxicity in mice and rats

被引:10
作者
Chen, Kaizhen [1 ]
Teo, Shiyi [1 ]
Seng, Kok -Yong [1 ]
机构
[1] DSO Natl Labs, Def Med & Environm Res Inst, Bioengn Lab, Singapore 117510, Singapore
关键词
Acetylcholinesterase; allometric scaling; diisopropylfluorophosphate; physiologically-based pharmacokinetic and pharmacodynamic model; sensitivity analysis; RISK-ASSESSMENT; INHIBITION; ACETYLCHOLINESTERASE; PLASMA; SOMAN; EXPOSURE; FORMS;
D O I
10.1080/15376510903300335
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
A physiologically-based pharmacokinetic and pharmacodynamic (PBPK/PD) model was recently developed to study the effect of diisopropylfluorophosphate (DFP) on acetylcholinesterase (AChE) activity in mouse and rat. That model takes into account relatively complex interactions involving many parameters, some of which may be uncertain and/or highly variable, especially those characterizing AChE activity after DFP intoxication. The primary objective of this study was to identify parameters that contribute most to the variability of AChE dynamics for model optimization against data. For this purpose, the influence of the variability of the rate constants for synthesis (K-syn) and degradation (K-deg) of AChE, and regeneration (K-reg) and aging (K-age) of inhibited AChE on the variability of AChE activity in mice and rat venous blood and brain was first calculated by a global sensitivity analysis. Next, the mouse PBPK/PD model was calibrated by optimizing the values of K-syn, K-deg, K-reg and K-age. Thereafter, scale-up of the DFP-induced AChE activity was performed from mouse to rat. Validation of the rat model was performed by comparing the time course of venous blood and brain AChE activities from a Monte Carlo analysis to those obtained in vivo. Sensitivity analysis on the verified models showed that K-reg and K-syn were the most influential factors of AChE activity at shorter and longer durations, respectively, after DFP challenge. Scale-up of the AChE dynamics from mouse to rat was also successful, as evidenced by significant overlapping between the predicted 95(th) percentile confidence intervals and the experimental data.
引用
收藏
页码:486 / 497
页数:12
相关论文
共 28 条
  • [1] Evaluation of HI 6 treatment after percutaneous VR exposure by use of a kinetic-based dynamic computer model
    Aurbek, N.
    Thiermann, H.
    Szinicz, L.
    Worek, F.
    [J]. TOXICOLOGY, 2007, 233 (1-3) : 173 - 179
  • [2] Characterizing uncertainty and variability in physiologically based pharmacokinetic models: State of the science and needs for research and implementation
    Barton, Hugh A.
    Chiu, Weihsueh A.
    Setzer, R. Woodrow
    Andersen, Melvin E.
    Bailer, A. John
    Bois, Frederic Y.
    DeWoskin, Robert S.
    Hays, Sean
    Johanson, Gunnar
    Jones, Nancy
    Loizou, George
    MacPhail, Robert C.
    Portier, Christopher J.
    Spendiff, Martin
    Tan, Yu-Mei
    [J]. TOXICOLOGICAL SCIENCES, 2007, 99 (02) : 395 - 402
  • [3] An integrated probabilistic framework for cumulative risk assessment of common mechanism chemicals in food: An example with organophosphorus pesticides
    Bosgra, Sieto
    van der Voet, Hilko
    Boon, Polly E.
    Slob, Wout
    [J]. REGULATORY TOXICOLOGY AND PHARMACOLOGY, 2009, 54 (02) : 124 - 133
  • [4] Physiological parameter values for physiologically based pharmacokinetic models
    Brown, RP
    Delp, MD
    Lindstedt, SL
    Rhomberg, LR
    Beliles, RP
    [J]. TOXICOLOGY AND INDUSTRIAL HEALTH, 1997, 13 (04) : 407 - 484
  • [5] ROLE OF ALIESTERASE IN ORGANO-PHOSPHATE POISONING
    CLEMENT, JG
    [J]. FUNDAMENTAL AND APPLIED TOXICOLOGY, 1984, 4 (02): : S96 - S105
  • [6] Development and specification of physiologically based pharmacokinetic models for use in risk assessment
    Clewell, Rebecca A.
    Clewell, Harvey J., III
    [J]. REGULATORY TOXICOLOGY AND PHARMACOLOGY, 2008, 50 (01) : 129 - 143
  • [7] Ecobichon DJ, 1996, CASARETT DOULLS TOXI, P890
  • [8] EPA, 2006, Final Report
  • [9] PHYSIOLOGICALLY BASED PHARMACOKINETIC AND PHARMACODYNAMIC MODEL FOR THE INHIBITION OF ACETYLCHOLINESTERASE BY DIISOPROPYLFLUOROPHOSPHATE
    GEARHART, JM
    JEPSON, GW
    CLEWELL, HJ
    ANDERSEN, ME
    CONOLLY, RB
    [J]. TOXICOLOGY AND APPLIED PHARMACOLOGY, 1990, 106 (02) : 295 - 310
  • [10] PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR THE INHIBITION OF ACETYLCHOLINESTERASE BY ORGANOPHOSPHATE ESTERS
    GEARHART, JM
    JEPSON, GW
    CLEWELL, HJ
    ANDERSEN, ME
    CONOLLY, RB
    [J]. ENVIRONMENTAL HEALTH PERSPECTIVES, 1994, 102 : 51 - 60