McMillan D E, Hardwick W C, Li M, Gunnell M G, Carroll F I, Abraham P, Owens S M
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72204, USA.
J Pharmacol Exp Ther. 2004 Jun;309(3):1248-55. doi: 10.1124/jpet.103.061762. Epub 2004 Mar 1.
Two murine-derived anti-methamphetamine monoclonal antibodies were studied as potential pharmacokinetic antagonists of (+)-methamphetamine self-administration by rats. Intravenous administration of a 1 g/kg dose of the lower affinity [antibody equilibrium dissociation constant (K(d)) = 250 nM] monoclonal antibody (mAb) designated mAb6H8, 1 day before the start of several daily 2-h self-administration sessions produced effects that depended on the dose of (+)-methamphetamine. mAb6H8 increased the rate of self-administration of a unit dose of 0.06 mg/kg (+)-methamphetamine, had little effect on the rate of self-administration of a unit dose of 0.03 mg/kg (+)methamphetamine, and lowered the rate of self-administration of a unit dose of 0.01 mg/kg (+)-methamphetamine to a level similar to that after saline substitution. mAb-induced changes in rates of self-administration occurred very early in self-administration sessions and lasted for 3 to 7 days. Intravenous administration of a 1 or a 0.6 g/kg dose of a higher affinity (K(d) = 11 nM) mAb designated mAb6H4, 24 h before the first of several self-administration sessions, produced very similar effects to the lower affinity mAb, despite the more than 20-fold greater affinity for (+)-methamphetamine. It is proposed that these anti-methamphetamine antibodies bind some of the self-administered (+)-methamphetamine before it can penetrate into brain, thereby reducing the amount of free drug available to function as a reinforcer. Although neither of these mAb medications are optimal antibodies for treating (+)-methamphetamine abuse, the experiments demonstrate that anti-(+)-methamphetamine monoclonal antibodies can attenuate the self-administration of the drug and suggest the potential of using monoclonal antibodies as pharmacokinetic antagonists of (+)-methamphetamine.
研究了两种鼠源抗甲基苯丙胺单克隆抗体，作为大鼠（+）-甲基苯丙胺自我给药的潜在药代动力学拮抗剂。在开始每日数次2小时自我给药疗程前1天，静脉注射1 g/kg剂量的低亲和力[抗体平衡解离常数（K(d)）= 250 nM]单克隆抗体（mAb），即mAb6H8，产生的效应取决于（+）-甲基苯丙胺的剂量。mAb6H8增加了0.06 mg/kg（+）-甲基苯丙胺单位剂量的自我给药速率，对0.03 mg/kg（+）-甲基苯丙胺单位剂量的自我给药速率影响不大，并将0.01 mg/kg（+）-甲基苯丙胺单位剂量的自我给药速率降低至与生理盐水替代后相似的水平。mAb引起的自我给药速率变化在自我给药疗程的早期就出现了，并持续3至7天。在首次自我给药疗程前24小时，静脉注射1或0.6 g/kg剂量的高亲和力（K(d) = 11 nM）mAb，即mAb6H4，产生了与低亲和力mAb非常相似的效应，尽管其对（+）-甲基苯丙胺的亲和力高出20多倍。据推测，这些抗甲基苯丙胺抗体在（+）-甲基苯丙胺能够渗透到大脑之前就结合了一些自我给药的（+）-甲基苯丙胺，从而减少了可作为强化剂发挥作用的游离药物量。尽管这两种mAb药物都不是治疗（+）-甲基苯丙胺滥用的最佳抗体，但实验表明抗（+）-甲基苯丙胺单克隆抗体可以减弱药物的自我给药，并提示了使用单克隆抗体作为（+）-甲基苯丙胺药代动力学拮抗剂的潜力。
