A chimeric human/murine anticocaine monoclonal antibody inhibits the distribution of cocaine to the brain in mice
A chimeric human/murine anticocaine monoclonal antibody inhibits the distribution of cocaine to the brain in mice
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DOI：
10.1124/jpet.106.111781
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发表时间：
2007-01-01
影响因子：
3.5
通讯作者：
Ball, William J.
中科院分区：
文献类型：
--
作者：
Norman, Andrew B.;Tabet, Michael R.;Ball, William J.
主要是人类序列，高亲和力抗可卡因单克隆抗体（mAb）2 E2从小鼠血液中清除缓慢的一级过程与消除t（1/2）为8.1天。输注的2 E2还产生了血浆可卡因浓度的显著剂量依赖性增加，并且伴随着由静脉注射可卡因HCl（0.56 mg/kg）产生的脑可卡因浓度的降低。在检测的2 E2最高剂量（3：1，mAb/药物）下，大脑中未检测到可卡因。药代动力学研究表明，血浆中可卡因的正常消失可用双室药代动力学模型描述，分布t（1/2 α）和终末消除t（1/2 β）值分别为1.9和26.1 min。在存在等摩尔剂量mAb 2 E2的情况下，血浆可卡因浓度-时间曲线下面积（AUC）相对于不存在2 E2的AUC增加了26倍。因此，2 E2将可卡因的分布容积从6.0 l/kg降低至0.20 l/kg，接近2 E2的分布容积（0.28 l/kg）。然而，可卡因仍能迅速从血浆中清除，其消除现在用单室模型描述，消除t（1/2）为17 min。重要的是，2 E2还使大脑中的可卡因AUC降低4.5倍（78%）。因此，2 E2对血浆和脑可卡因浓度的影响主要是由可卡因分布的变化引起的，对其清除率的影响可忽略不计。这些数据支持药物滥用免疫疗法的概念。
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 HCI (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(1/2 alpha) and terminal elimination t(1/2 beta) 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.