Use of a physiologically based pharmacokinetic model for rats to study the influence of body fat mass and induction of CYP1A2 on the pharmacokinetics of TCDD.
Use of a physiologically based pharmacokinetic model for rats to study the influence of body fat mass and induction of CYP1A2 on the pharmacokinetics of TCDD.
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使用基于生理学的大鼠药代动力学模型研究体脂肪量和 CYP1A2 诱导对 TCDD 药代动力学的影响。
DOI：
10.1289/ehp.8805
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发表时间：
2006-09
影响因子：
10.4
通讯作者：
DeVito, Michael J.
中科院分区：
文献类型：
--
作者：
Emond, Claude;Birnbaum, Linda S.;DeVito, Michael J.
2，3，7，8-四氯二苯并-对-二恶英（TCDD）是一种高度亲脂性的化学物质，特别是在低剂量时，会分布到脂肪组织中。然而，在高剂量下，TCDD螯合在肝脏中，因为它诱导细胞色素P450 1A 2（CYP 1A 2）结合TCDD。一个基于生理的药代动力学（PBPK）模型，包括诱导消除率的TCDD在Sprague-Dawley大鼠。本工作的目的是表征的CYP 1A 2和脂肪组织的质量分数的诱导TCDD的终末消除半衰期（t1/2）的影响，使用该PBPK模型。当模型假设TCDD的消除是固定的时，由于肝隔离，t1/2随剂量增加而增加。由于实验数据表明TCDD的t1/2随剂量而降低，因此对模型进行了修改，以包括诱导消除率。然后使用PBPK模型比较脂肪组织质量分数从6.9%增加到70%后的t1/2。该模型表明，在低暴露下，增加脂肪组织质量会增加终末t1/2。然而，在较高的暴露量下，随着CYP 1A 2被诱导，脂肪组织质量与t1/2之间的关系达到平台。这表明在PBPK模型中需要一个可诱导的消除速率来描述TCDD的药代动力学。在低暴露下，这些模型对与分配到脂肪组织有关的参数更敏感。
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly lipophilic chemical that distributes into adipose tissue, especially at low doses. However, at high doses TCDD sequesters in liver because it induces cytochrome P450 1A2 (CYP1A2) that binds TCDD. A physiologically based pharmacokinetic (PBPK) model was developed that included an inducible elimination rate of TCDD in the Sprague-Dawley rat. Objectives of this work were to characterize the influence of induction of CYP1A2 and adipose tissue mass fraction on the terminal elimination half-life (t1/2) of TCDD using this PBPK model. When the model assumes a fixed elimination of TCDD, t1/2 increases with dose, due to hepatic sequestration. Because experimental data indicate that the t1/2 of TCDD decreases with dose, the model was modified to include an inducible elimination rate. The PBPK model was then used to compare the t1/2 after an increase of adipose tissue mass fraction from 6.9 to 70%. The model suggests that at low exposures, increasing adipose tissue mass increases the terminal t1/2. However, at higher exposures, as CYP1A2 is induced, the relationship between adipose tissue mass and t1/2 reaches a plateau. This demonstrates that an inducible elimination rate is needed in a PBPK model in order to describe the pharmacokinetics of TCDD. At low exposures these models are more sensitive to parameters related to partitioning into adipose tissue.
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影响因子：
6.7
作者：
Abraham, K;Geusau, A;Brockmöller, J
通讯作者：
Brockmöller, J
影响因子：
3.8
作者：
Andersen, ME;Birnbaum, LS;Eklund, CR
通讯作者：
Eklund, CR
影响因子：
3.8
作者：
CARRIER, G;BRUNET, RC;BRODEUR, J
通讯作者：
BRODEUR, J
影响因子：
8.8
作者：
Moser, GA;McLachlan, MS
通讯作者：
McLachlan, MS
DOI：
10.1111/j.1600-0773.1990.tb00712.x
发表时间：
1990-02-01
期刊：
PHARMACOLOGY & TOXICOLOGY
影响因子：
--
作者：
POHJANVIRTA, R;VARTIAINEN, T;TUOMISTO, J
通讯作者：
TUOMISTO, J