Pharmacokinetic factors and concentration-time threshold in m-dinitrobenzene-induced neurotoxicity.
Pharmacokinetic factors and concentration-time threshold in m-dinitrobenzene-induced neurotoxicity.
复制标题
间二硝基苯引起的神经毒性的药代动力学因素和浓度-时间阈值。
DOI：
10.1006/taap.1999.8805
复制
发表时间：
1999
影响因子：
3.8
通讯作者：
D. E. Ray
中科院分区：
文献类型：
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作者：
J. Xu;C. Nolan;T. Lister;W. Purcell;D. E. Ray
间二硝基苯是一种多靶毒物。本研究基于药代动力学模型和具有神经病理学终点的可变持续时间输注，提出了间二硝基苯（m-DNB）诱导的F344大鼠神经毒性的浓度-时间阈值模型。单次静脉注射10 mg/kg m-DNB后，测定m-DNB的药代动力学参数。通过单次静脉推注30 mg/kg m-DNB或在6、12或24 h或2、4、6、8或14天内输注该剂量，研究脑损伤的时间依赖性。结果表明，6天输注（其中理论稳态血药浓度为2.0 μ M）引起脑损伤，而8天和14天输注（其中稳态血药浓度分别为1.5和0.8 μ M）未引起明显的脑损伤。当该剂量输注超过6小时时，m-DNB的峰值血液浓度为35 μ M，m-DNB超过2 μ M浓度阈值的时间（T（m））为18.8小时，但未观察到脑损伤。然而，当在12或24小时或2、4或6天内输注相同的总剂量时，理论血药浓度为21.9至2.0 μ M，T（m）为22。7 ~ 144 h，造成脑损伤。因此，认为22.7 h的T（m）是m-DNB诱导脑损伤的时间阈值。它的结论是，单独的高浓度不会导致间二硝基苯诱导的神经毒性，除了浓度阈值，也存在一个时间阈值。显然，在看到神经毒性之前，两者都需要超过。
m-Dinitrobenzene is a multitarget toxicant. This study presents a concentration-time threshold model in m-dinitrobenzene (m-DNB)-induced neurotoxicity in F344 rats based on pharmacokinetic modeling and variable duration infusions with neuropathological end points. Pharmacokinetic parameters for m-DNB were determined after giving a single i.v. dose of 10 mg/kg m-DNB. Time dependency of the brain lesions was studied by either giving a single bolus i.v. dose of 30 mg/kg m-DNB or infusing this dose over 6, 12, or 24 h, or 2, 4, 6, 8, or 14 days. The results show that the 6-day infusion, in which the theoretical steady-state blood concentration was 2.0 microM, caused brain damage, whereas the 8- and 14-day infusions, in which the steady-state blood concentrations were 1.5 and 0.8 microM, respectively, did not induce apparent brain damage. When this dose was infused over 6 h, the peak blood concentration of m-DNB was 35 microM and the time (T(m)) for which m-DNB exceeded the 2-microM concentration threshold was 18.8 h, but no brain damage was observed. However, when the same total dosage was infused over periods of either 12 or 24 h, or 2, 4, or 6 days, the theoretical blood concentrations were from 21.9 to 2.0 microM and the T(m) was from 22. 7 to 144 h, and brain damage was produced. Hence a T(m) of 22.7 h was considered to be the time threshold for m-DNB-induced brain damage. It is concluded that a high concentration alone does not result in m-DNB-induced neurotoxicity and that in addition to a concentration threshold, there also exists a time threshold. Both apparently need to be exceeded before neurotoxicity is seen.
1,3-二硝基苯在大鼠和仓鼠中的代谢和药代动力学。
DOI：
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发表时间：
1991
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
McEuen,SF;Miller,MG
通讯作者：
Miller,MG
DOI：
10.1080/15287398109530024
发表时间：
1981-01-01
期刊：
JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH
影响因子：
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作者：
CODY, TE;WITHERUP, S;CHRISTIAN, RT
通讯作者：
CHRISTIAN, RT