Ikeda T, Tsuda S, Shirasu Y
Mitsukaido Laboratories, Institute of Environmental Toxicology, Ibaraki, Japan.
Fundam Appl Toxicol. 1992 Feb;18(2):299-306. doi: 10.1016/0272-0590(92)90059-q.
We have previously reported that the acute oral toxicity of chlorfenvinphos (CVP) is reduced by the oral pretreatment of rats with the same compound. In this report, the mechanism of this protection was clarified mainly through the physiologically based pharmacokinetic analysis. The CVP pretreatment (15 mg/kg, po, 24 hr before) reduced the lethality of po CVP greatly, and that of iv CVP to a lesser extent. Brain acetylcholinesterase inhibition by po and iv CVP was also decreased by the pretreatment. The magnitude of reduction of the inhibition caused by the po CVP was greater than that of the iv CVP. The ratio of CVP concentration between the brain and plasma was the same, regardless of the route of administration or the pretreatment. The pretreatment greatly reduced the plasma concentration and the area under the plasma concentration versus time curve (AUC) of the po CVP, but did not change appreciably that of the iv CVP. The unbound fraction of CVP in the blood or the liver was not changed by the pretreatment. According to physiologically based pharmacokinetic analysis, the decrease in AUC of the po CVP may be mainly caused by an increase in intrinsic clearance of the liver and a decrease in the partition coefficient of CVP between the emergent blood and the liver. The increase in the intrinsic clearance may be related to the metabolic induction observed in vitro. The pretreatment decreased the absorption rate constant of the po CVP. This change in combination with the above two factors which reduce AUC might be the reason for the decrease in the plasma concentration after the po CVP, and the protection against the CVP toxicity of the succeeding dosage.
我们之前报道过，用毒死蜱（CVP）对大鼠进行口服预处理可降低其急性经口毒性。在本报告中，主要通过基于生理学的药代动力学分析阐明了这种保护作用的机制。CVP预处理（15mg/kg，口服，提前24小时）大大降低了经口给予CVP的致死率，对静脉注射CVP致死率的降低程度较小。预处理还降低了经口和静脉注射CVP对脑乙酰胆碱酯酶的抑制作用。经口给予CVP所导致的抑制作用的降低幅度大于静脉注射CVP。无论给药途径或预处理如何，脑与血浆中CVP浓度的比值相同。预处理大大降低了经口给予CVP后的血浆浓度以及血浆浓度-时间曲线下面积（AUC），但对静脉注射CVP的AUC没有明显影响。预处理未改变血液或肝脏中CVP的游离分数。根据基于生理学的药代动力学分析，经口给予CVP后AUC的降低可能主要是由于肝脏内在清除率的增加以及CVP在流出血液与肝脏之间分配系数的降低。内在清除率的增加可能与体外观察到的代谢诱导有关。预处理降低了经口给予CVP的吸收速率常数。这种变化与上述降低AUC的两个因素相结合，可能是经口给予CVP后血浆浓度降低以及对后续剂量CVP毒性产生保护作用的原因。
