Langenberg J P, Spruit H E, van der Wiel H J, Trap H C, Helmich R B, Bergers W W, van Helden H P, Benschop H P
TNO Prins Maurits Laboratory, Rijswijk, 2280 AA, The Netherlands.
Toxicol Appl Pharmacol. 1998 Jul;151(1):79-87. doi: 10.1006/taap.1998.8451.
The toxicokinetics of the four stereoisomers of the nerve agent C(+/-)P(+/-)-soman were studied in anesthetized, atropinized guinea pigs for nose-only exposure to soman vapor. During exposure the respiratory minute volume (RMV) and respiratory frequency (RF) were monitored. Blood samples were taken for chiral gas chromatographic analysis of the concentrations of nerve agent stereoisomers and for measurement of the progressive inhibition of acetylcholinesterase (AChE). The animals were exposed for 4-8 min to 0.4-0.8 LCt50 of C(+/-)P(+/-)-soman. Concentrations of the P(-)-isomers increased rapidly during exposure, up to several nanograms per milliliter of blood. Mathematical equations describing the concentration-time courses of the P(-)-isomers were obtained by nonlinear regression. The kinetics were mathematically described as a discontinuous process, with a monoexponential equation for the exposure period and a two-exponential equation for the postexposure period. The absorption phase of C(+)P(-)-soman lagged behind that of the C(-)P(-)-isomer, presumably due to preferential covalent binding at as yet unidentified binding sites. The terminal half-life observed after nose-only exposure is longer than that observed after an equitoxic iv bolus administration, which suggests the presence of a depot in the upper respiratory tract from which absorption continues after termination of the exposure. Two types of nonlinearity of the toxicokinetics were observed, i.e., with dose and with exposure time. The AChE activity was rapidly inhibited during exposure to the nerve agent vapor. There were no soman-related effects on RMV and RF. The toxicokinetics of the soman stereoisomers observed for nose-only exposure are compared with those determined for iv bolus and sc administration.
在麻醉且已用阿托品处理的豚鼠身上，研究了神经性毒剂C(+/-)P(+/-)-梭曼四种立体异构体的毒代动力学，使其仅通过鼻腔暴露于梭曼蒸气中。暴露期间监测呼吸分钟通气量（RMV）和呼吸频率（RF）。采集血样，用于对神经性毒剂立体异构体浓度进行手性气相色谱分析，并测量乙酰胆碱酯酶（AChE）的渐进性抑制情况。将动物暴露于0.4 - 0.8 LCt50的C(+/-)P(+/-)-梭曼中4 - 8分钟。暴露期间，P(-)-异构体的浓度迅速升高，可达每毫升血液数纳克。通过非线性回归获得了描述P(-)-异构体浓度-时间过程的数学方程。动力学在数学上被描述为一个不连续过程，暴露期用单指数方程描述，暴露后用双指数方程描述。C(+)P(-)-梭曼的吸收阶段滞后于C(-)P(-)-异构体，推测是由于在尚未确定的结合位点存在优先共价结合。仅通过鼻腔暴露后观察到的终末半衰期长于等毒性静脉推注给药后观察到的半衰期，这表明上呼吸道存在一个储存库，暴露终止后仍可继续吸收。观察到毒代动力学的两种非线性情况，即与剂量和暴露时间有关。暴露于神经性毒剂蒸气期间，AChE活性迅速受到抑制。未观察到与梭曼相关的对RMV和RF的影响。将仅通过鼻腔暴露观察到的梭曼立体异构体的毒代动力学与静脉推注和皮下给药所确定的毒代动力学进行了比较。
