Disposition of butanal oxime in rat following oral, intravenous and dermal administration.
Disposition of butanal oxime in rat following oral, intravenous and dermal administration.
复制标题
口服、静脉内和皮肤给药后丁醛肟在大鼠体内的处置。
DOI：
10.1080/004982598239182
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Burka,LT
中科院分区：
文献类型：
--
作者：
Mathews,JM;Black,SR;Burka,LT
1.经口、静脉和皮肤给药后，测定了[1- 14 C]丁醛肟（BOX）在大鼠中的处置。2.经口给药的[14 C]BOX（2和20 mg/kg）主要经尿液排泄（> 42%），并转化为14 CO2（> 30%），给药后72 h约有10%的剂量残留在组织中。3.皮肤剂量为2和20 mg/kg的BOX分别有8%和16%被吸收，部分原因是皮肤表面的快速挥发。4.口服剂量的BOX转化为几种极性和/或阴离子代谢产物，包括硫酸盐结合物和大量硫氰酸盐。5.以1-氨基苯并三唑（ABT）和反式-1，2-二氯乙烯（DCE）为抑制剂，研究了它们对BOX代谢的影响。DCE和ABT处理组大鼠尿中未检测到硫氰酸根阴离子。ABT显著增加14 CO2的产生和挥发性代谢产物的排泄。DCE对14 CO2排出无影响，但增加了放射性标记物的排出。ABT还有效地阻断了近致死剂量BOX引起的大鼠氰化物毒性效应的表达。6.这些数据与BOX的两种不同代谢途径一致，（1）还原为亚胺、水解和随后丁醛转化为14 CO2和（2）CYP 3A催化BOX脱水为丁腈，随后CYP 2 E1催化氰化物释放。
1. The disposition of [1-14C]butanal oxime (BOX) was determined in the rat after oral, i.v. and dermal administration. 2. Oral doses of [14C]BOX (2 and 20 mg/kg) were predominantly excreted in the urine (> 42%) and converted to14CO2(> 30%) and about 10% of the dose remained in the tissues 72 h post-dosing. 3. Eight and 16% of a 2 and 20 mg/kg dermal dose of BOX, respectively, were absorbed, due in part to rapid volatilization from the surface of the skin. 4. Oral doses of BOX were transformed into several polar and/or anionic metabolites that include sulphate conjugates and a significant amount of thiocyanate. 5. The effect of inhibitors on the metabolism of BOX was investigated using 1- aminobenzotriazole (ABT; an inhibitor of diverse cytochrome P450s) andtrans-1,2- dichloroethylene (DCE; an inhibitor of CYP2E1). No thiocyanate anion was detected in the urine of rat treated with DCE or ABT. ABT markedly increased the production of14CO2and excretion as volatile metabolites. DCE had no effect on14CO2excretion, but increased exhalation of radiolabel. ABT also effectively blocked the expression of toxic effects attributable to cyanide in rat given near-lethal doses of BOX. 6. The data are consistent with two distinct pathways of metabolism for BOX, (1) reduction to an imine, hydrolysis and subsequent conversion of butyraldehyde to14CO2and (2) CYP3A-catalysed dehydration of BOX to butyronitrile followed by CYP2E1- catalysed release of cyanide.