Bueters Tjerk J H, IJzerman Ad P, van Helden Herman P M, Danhof Meindert
Research Group Medical Countermeasures, TNO Prins Maurits Laboratory, Lange Kleiweg 137, PO Box 45, 2280 AA Rijswijk, The Netherlands.
Toxicol Appl Pharmacol. 2003 Oct 1;192(1):86-94. doi: 10.1016/s0041-008x(03)00252-7.
The objective of the present study was to determine (1) the influence of sarin poisoning (144 microg/kg s.c.) on the pharmacokinetics and brain distribution of the adenosine A1 receptor partial agonist 2'-deoxy-N6-cyclopentyladenosine (2'dCPA), and (2) the effect of 2'dCPA (20 mg/kg i.v.) on the central acetylcholine (ACh) release and protection against sarin toxicity. A five-compartment model successfully described the pharmacokinetic profile of 2'dCPA in blood and brain microdialysate. A covariate analysis revealed that the volume of distribution of 2'dCPA in blood was different in sarin-poisoned rats, 177 +/- 7 versus 148 +/- 8 ml in control rats. However, the transport of 2'dCPA from blood to the brain was unaffected as reflected by the values of the intercompartmental transport clearances, 0.21 +/- 0.02 and 0.21 +/- 0.04 microl/min in control and sarin-poisoned rats, respectively. Also the area-under-curve (AUC) ratios of brain microdialysate and blood were identical with values of 0.02 +/- 0.001 and 0.02 +/- 0.002, respectively, demonstrating the restricted transport of 2'dCPA into the brain in both treatment groups. Treatment of sarin-poisoned rats by 2'dCPA did not adequately prevent the accumulation of ACh in the central nervous system. 2'dCPA delayed the emergence of concomitant symptoms compared to untreated rats, but eventually only 29% of the animals survived 24 h. In conclusion, the pharmacokinetic profile of 2'dCPA in blood was slightly changed by sarin, but not the distribution of 2'dCPA into the brain. The therapeutic efficacy of 2'dCPA against sarin was limited, presumably due to insufficient quantities of 2'dCPA reaching the brain.
（1）沙林中毒（144微克/千克皮下注射）对腺苷A1受体部分激动剂2'-脱氧-N6-环戊基腺苷（2'dCPA）药代动力学和脑部分布的影响；（2）2'dCPA（20毫克/千克静脉注射）对中枢乙酰胆碱（ACh）释放及沙林毒性防护的作用。一个五房室模型成功描述了2'dCPA在血液和脑微透析液中的药代动力学特征。协变量分析显示，沙林中毒大鼠血液中2'dCPA的分布容积不同，对照组大鼠为148±8毫升，沙林中毒大鼠为177±7毫升。然而，2'dCPA从血液到脑的转运未受影响，对照组和沙林中毒大鼠的房室间转运清除率值分别为0.21±0.02和0.21±0.04微升/分钟。脑微透析液与血液的曲线下面积（AUC）比值也相同，分别为0.02±0.001和0.02±0.002，表明两个治疗组中2'dCPA进入脑内的转运均受限。用2'dCPA治疗沙林中毒大鼠不能充分预防中枢神经系统中ACh的蓄积。与未治疗大鼠相比，2'dCPA延迟了伴随症状的出现，但最终只有29%的动物存活24小时。总之，沙林使2'dCPA在血液中的药代动力学特征略有改变，但未改变2'dCPA在脑内的分布。2'dCPA对沙林的治疗效果有限，可能是由于到达脑内的2'dCPA量不足。
