A Chimeric Human/Murine Anticocaine Monoclonal Antibody Inhibits the Distribution of Cocaine to the Brain in Mice
| Autor: | William J. Ball, Mantana K. Norman, William R. Buesing, Amadeo J. Pesce, Andrew B. Norman, Michael R. Tabet |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Drug medicine.drug_class Recombinant Fusion Proteins media_common.quotation_subject medicine.medical_treatment Molecular Sequence Data Pharmacology Monoclonal antibody Cocaine-Related Disorders Mice Cocaine Pharmacokinetics medicine Animals Humans Distribution (pharmacology) Tissue Distribution Amino Acid Sequence media_common Volume of distribution Dose-Response Relationship Drug Chemistry Antibodies Monoclonal Brain Immunotherapy Concomitant Molecular Medicine Clearance |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 320:145-153 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.106.111781 |
| Popis: | 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 1/2α and terminal elimination t 1/2β 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. |
| Databáze: | OpenAIRE |
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