A chimeric human/murine anticocaine monoclonal antibody inhibits the distribution of cocaine to the brain in mice.
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.
Norman
Andrew B
AB
Division of Neuroscience, Department of Psychiatry, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0559, USA. andrew.norman@uc.edu
Tabet
Michael R
MR
Norman
Mantana K
MK
Buesing
William R
WR
Pesce
Amadeo J
AJ
Ball
William J
WJ
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism*; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics*; D019970:Cocaine-Related Disorders / Q000628:therapy; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D011993:Recombinant Fusion Proteins; D003042:Cocaine