Abstract
These studies examined the effects of a high-affinity anti-(+)-methamphetamine monoclonal antibody (mAb; KD = 11 nM) on (+)-methamphetamine [(+)-METH] and (+)-amphetamine [(+)-AMP] serum and tissue disposition and serum protein binding following i.v. (+)-METH administration. Male Sprague-Dawley rats were pretreated with a buffer solution (control rats) or with anti-(+)-METH mAb [equimolar in binding sites to the (+)-METH dose]. The next day, both groups received a 1 mg/kg i.v. (+)-METH dose. At various time points after (+)-METH administration, rats were sacrificed (n = 3 per time point), and serum and tissues were collected. (+)-METH serum protein binding was increased from ∼5% in controls to ∼88 to 99% in the mAb-treated rats. The (+)-METH area under the concentration versus time curves from 0 to 4.5 h (AUC04.5 h) in mAb-treated rats showed an increase of >6600% for serum and a decrease of >60% for brain, compared with buffer-treated controls. Differential effects of anti-METH mAb on (+)-METH concentrations were observed in other tissues. For example, in the liver, anti-(+)-METH mAb caused significant increases in (+)-METH concentrations. The AUC04.5 h for (+)-AMP, a pharmacologically active metabolite, was decreased by ∼50% in all tissues examined. These data show that pretreatment with an anti-(+)-METH mAb can significantly alter the disposition of (+)-METH and (+)-AMP in rats. Since the mAb has no significant cross-reactivity with (+)-AMP, the data suggest that the mAb reduced (+)-METH metabolic clearance through high-affinity binding to (+)-METH. Finally, rapidly equilibrating tissues, like the brain, appear to be preferentially protected by the mAb.
Footnotes
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↵1 Present address: ZymoGenetics, Inc., 1201 Eastlake Ave. E, Seattle, WA 98102.
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↵2 Abbreviations used are: mAb, monoclonal antibody; Fab, antigen binding fragment; Vd, volume of distribution; (+)-METH, (+)-methamphetamine; PCP, phencyclidine; (+)-AMP, (+)-amphetamine; AUC, area under the concentration-versus-time curve; t1/2λZ, terminal elimination half-life; HPLC, high-performance liquid chromatography.
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This work was supported by National Institute on Drug Abuse Grants DA11560 and PO1 DA14361 to S. M. Owens, Grant DA0339 to W. B. Gentry, and Grant F31 DA05939 to K. A. Byrnes-Blake.
- Received March 24, 2003.
- Accepted July 30, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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