Norman Andrew B, Tabet Michael R, Norman Mantana K, Buesing William R, Pesce Amadeo J, Ball William J
Division of Neuroscience, Department of Psychiatry, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0559, USA.
J Pharmacol Exp Ther. 2007 Jan;320(1):145-53. doi: 10.1124/jpet.106.111781. Epub 2006 Oct 5.
The predominantly human sequence, high-affinity anticocaine monoclonal antibody (mAb) 2E2 was cleared slowly from mouse blood by a first-order process with an elimination t(1/2) of 8.1 days. Infused 2E2 also produced a dramatic dose-dependent increase in plasma cocaine concentrations and a concomitant decrease in the brain cocaine concentrations produced by an i.v. injection of cocaine HCl (0.56 mg/kg). At the highest dose of 2E2 tested (3:1, mAb/drug), cocaine was not detectable in the brain. Pharmacokinetic studies showed that the normal disappearance of cocaine from plasma was described by a two-compartment pharmacokinetic model with distribution t(1/2alpha) and terminal elimination t(1/2beta) values of 1.9 and 26.1 min, respectively. In the presence of an equimolar dose of mAb 2E2, there was a 26-fold increase in the area under the plasma cocaine concentration-time curve (AUC) relative to the AUC in the absence of 2E2. Consequently, 2E2 decreased the volume of distribution of cocaine from 6.0 to 0.20 l/kg, which approximated that of 2E2 (0.28 l/kg). However, cocaine was still rapidly cleared from plasma, and its elimination was now described by a single-compartment model with an elimination t(1/2) of 17 min. Importantly, 2E2 also produced a 4.5-fold (78%) decrease in the cocaine AUC in the brain. Therefore, the effect of 2E2 on plasma and brain cocaine concentrations was predominantly caused by a change in the distribution of cocaine with negligible effects on its rate of clearance. These data support the concept of immunotherapy for drug abuse.
主要为人源序列的高亲和力抗可卡因单克隆抗体（mAb）2E2 从鼠血中清除缓慢，呈一级动力学过程，消除半衰期（t(1/2)）为 8.1 天。静脉输注 2E2 还使血浆可卡因浓度显著增加，且呈剂量依赖性，同时静脉注射盐酸可卡因（0.56 mg/kg）后产生的脑内可卡因浓度随之降低。在测试的 2E2 最高剂量（抗体/药物为 3:1）下，脑内未检测到可卡因。药代动力学研究表明，可卡因从血浆中的正常消除过程可用二室药代动力学模型描述，分布半衰期（t(1/2α)）和终末消除半衰期（t(1/2β)）分别为 1.9 分钟和 26.1 分钟。在存在等摩尔剂量的 mAb 2E2 时，血浆可卡因浓度-时间曲线下面积（AUC）相对于不存在 2E2 时增加了 26 倍。因此，2E2 使可卡因的分布容积从 6.0 降至 0.20 l/kg，接近 2E2 的分布容积（0.28 l/kg）。然而，可卡因仍从血浆中快速清除，其消除现可用单室模型描述，消除半衰期为 17 分钟。重要的是，2E2 还使脑内可卡因 AUC 降低了 4.5 倍（78%）。因此，2E2 对血浆和脑内可卡因浓度的影响主要是由可卡因分布的改变引起的，对其清除速率的影响可忽略不计。这些数据支持了药物滥用免疫治疗的概念。
