van der Schans Marcel J, Lander Brenda J, van der Wiel Herma, Langenberg Jan P, Benschop Hendrik P
Division Chemical and Biological Protection, TNO Prins Maurits Laboratory, PO Box 45, 2280 AA, Rijswijk, The Netherlands.
Toxicol Appl Pharmacol. 2003 Aug 15;191(1):48-62. doi: 10.1016/s0041-008x(03)00216-3.
In continuation of our investigations on the toxicokinetics of the volatile nerve agents C(+/-)P(+/-)-soman and (+/-)-sarin, we now report on the toxicokinetics of the rather nonvolatile agent (+/-)-VX. A validated method was developed to determine blood levels of (+/-)-VX by means of achiral gas chromatography at blood levels > or =10 pg/ml. The ratio of the two enantiomers of VX in blood could be measured at levels > or =1 ng/ml by using chiral HPLC in combination with off-line gas chromatographic analysis. In order to obtain basic information on the toxicokinetics of (+/-)-VX, i.e., under conditions of 100% bioavailability, the blood levels of this agent were measured in hairless guinea pigs at iv doses corresponding with 1 and 2 LD50. The derived AUCs indicate a reasonable linearity of the toxicokinetics with dose. Also, the toxicokinetics in marmoset primates was studied at an absolute iv dose corresponding with 1 LD50 in the hairless guinea pig which led to approximately the same levels of (+/-)-VX in blood as observed at 2 LD50 in the hairless guinea pig. Finally, the toxicokinetics of (+/-)-VX were measured in hairless guinea pigs via the most relevant porte d' entrée for this agent, which is the percutaneous route at a dose corresponding with 1 LD50 (pc). Large variations were observed between individual animals in the rate of penetration of (+/-)-VX and in concomitant progression of AChE inhibition in blood of these animals. Blood levels of (+/-)-VX increased gradually over a 6-h period of time. After a 7-h penetration period, the total AUC corresponded with 2.5% bioavailability relative to iv administration. In contrast with the G-agents C(+/-)P(+/-)-soman and (+/-)-sarin, stereospecificity in the sequestration of the two enantiomers of (+/-)-VX is not a prominent phenomenon. It appears that (+/-)-VX is substantially more persistent in vivo than the two G-agents. This persistence may undermine the efficacy of pretreatment with carbamates of percutaneous intoxication in particular due to gradual replacement of carbamate on AChE by (+/-)-VX, whereas classical treatment of intoxication with oximes is hampered by the short persistence of oximes relative to the agent.
在对挥发性神经毒剂C(+/-)P(+/-)-梭曼和(+/-)-沙林毒代动力学研究的延续中，我们现在报告相对不挥发的毒剂(+/-)-VX的毒代动力学。开发了一种经过验证的方法，通过非手性气相色谱法测定血液中(+/-)-VX的水平，检测限为血液水平≥10 pg/ml。通过使用手性高效液相色谱结合离线气相色谱分析，可在血液中(+/-)-VX水平≥1 ng/ml时测量其两种对映体的比例。为了获取关于(+/-)-VX毒代动力学的基础信息，即在100%生物利用度的条件下，在无毛豚鼠中静脉注射相当于1和2个半数致死剂量（LD50）的剂量后测量该毒剂的血液水平。得到的曲线下面积（AUC）表明毒代动力学与剂量具有合理的线性关系。此外，在狨猴灵长类动物中研究了毒代动力学，静脉注射的绝对剂量相当于无毛豚鼠中的1个LD50，这导致血液中(+/-)-VX的水平与无毛豚鼠中2个LD50时观察到的水平大致相同。最后，在无毛豚鼠中通过该毒剂最相关的进入途径——经皮途径，以相当于1个经皮LD50（pc）的剂量测量(+/-)-VX的毒代动力学。在这些动物中，观察到(+/-)-VX的渗透速率以及伴随的血液中乙酰胆碱酯酶（AChE）抑制进展在个体动物之间存在很大差异。(+/-)-VX的血液水平在6小时内逐渐升高。经过7小时的渗透期后，相对于静脉给药，总AUC相当于2.5%的生物利用度。与G类毒剂C(+/-)P(+/-)-梭曼和(+/-)-沙林不同，(+/-)-VX两种对映体螯合中的立体特异性不是一个突出现象。看来(+/-)-VX在体内的持久性明显高于这两种G类毒剂。这种持久性可能会削弱氨基甲酸盐对经皮中毒预处理的效果，特别是由于(+/-)-VX会逐渐取代AChE上的氨基甲酸盐，而经典的肟类中毒治疗因肟类相对于该毒剂的持久性较短而受到阻碍。
