Pharmacokinetics of three novel pyridinium aldoxime acetylcholinesterase reactivators in female rats.
Pharmacokinetics of three novel pyridinium aldoxime acetylcholinesterase reactivators in female rats.
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三种新型吡啶醛肟乙酰胆碱酯酶再激活剂在雌性大鼠体内的药代动力学。
DOI：
10.1016/j.taap.2022.116046
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发表时间：
2022-07-01
影响因子：
3.8
通讯作者：
Chambers JE
中科院分区：
文献类型：
--
作者：
Backer BS;Meek EC;Ross MK;Chambers JE
发明了一种新的亲脂性取代的苯氧基烷基吡啶肟平台，以重新激活有机磷酸酯抑制的乙酰胆碱酯酶。对于致死剂量的神经毒剂替代物的存活以及脑渗透和神经保护的证据，该平台在大鼠中提供了优于当前护理标准2-PAM的上级功效。研究了三种新型肟在雌性大鼠中的药代动力学，以与雄性大鼠中的先前数据进行比较。与2-PAM的已发表半衰期（小于2小时）相比，新型肟（肟20）的先导化合物在肌肉注射给药后，在两种性别大鼠中的血浆半衰期约为5小时。药代动力学参数的性别差异非常明显。在雄性大鼠肌肉注射给药后的最初2小时内，肟20的脑浓度相对于血浆浓度增加，在1小时达到平台期; 2小时时两种性别之间的脑浓度无差异。肟20在大鼠微粒体中的肝脏代谢高于人微粒体。相对较长的血浆半衰期可能是之前观察到的肟20的存活率提高和神经保护作用的重要因素。代谢数据表明，肟20在人体中的清除率可能比在大鼠中观察到的要慢，这可能允许在治疗有机磷急性毒性时，给药频率低于2-PAM。因此，药代动力学数据结合我们早期的疗效数据表明，肟20有潜力作为神经毒剂中毒的上级治疗剂。
A platform of novel lipophilic substituted phenoxyalkyl pyridinium oximes was invented to reactivate organophosphate-inhibited acetylcholinesterase. This platform has provided superior efficacy in rats to the current standard of care, 2-PAM, for survival of lethal doses of nerve agent surrogates as well as evidence of brain penetration and neuroprotection. The pharmacokinetics of three of these novel oximes in female rats was studied for comparison to previous data in male rats. Compared to the published half-life of 2-PAM (less than 2 hours), the lead novel oxime, Oxime 20, displayed a plasma half-life of about 5 hours in both sexes of rats following intramuscular administration. Very few sex differences in pharmacokinetic parameters were apparent. Oxime 20 displayed an increase in brain concentration to plasma concentration over the initial 2 hours following intramuscular administration in male rats, with a plateau at 1 hour; there were no differences in brain concentrations between the sexes at 2 hours. Hepatic metabolism of Oxime 20 was higher in rat microsomes than in human microsomes. The relatively long plasma half-life is likely an important factor in both the enhanced survival and the neuroprotection previously observed for Oxime 20. The metabolism data suggest that the clearance of Oxime 20 could be slower in humans than was observed in rats, which might allow less frequent administration than 2-PAM for therapy of organophosphate acute toxicity. Therefore, the pharmacokinetic data combined with our earlier efficacy data suggest that Oxime 20 has potential as a superior therapeutic for nerve agent poisoning.
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影响因子：
3.8
作者：
Dail, Mary B.;Leach, Charles A.;Chambers, Janice E.
通讯作者：
Chambers, Janice E.
影响因子：
3.8
作者：
ALIOTHSTREICHENBERG, CM;BODMER, DM;WASER, PG
通讯作者：
WASER, PG
影响因子：
6.1
作者：
GREEN, MD;TALBOT, BG;CLARK, CR
通讯作者：
CLARK, CR
影响因子：
5.1
作者：
Chambers, Janice E.;Chambers, Howard W.;Ross, Matthew K.
通讯作者：
Ross, Matthew K.
影响因子：
4.3
作者：
Holstege, CP;Kirk, M;Sidell, FR
通讯作者：
Sidell, FR