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USE OF ANTI-(+)-METHAMPHETAMINE MONOCLONAL ANTIBODY TO SIGNIFICANTLY ALTER (+)-METHAMPHETAMINE AND (+)-AMPHETAMINE DISPOSITION IN RATS

Department of Pharmacology and Toxicology (E.M.L., K.A.B.-B., A.M.-H., W.B.G., S.M.O.), Department of Anesthesiology (W.B.G.), and Department of Biostatistics (D.K.W.), University of Arkansas for Medical Sciences, Little Rock, Arkansas

These studies examined the effects of a high-affinity anti-(+)-methamphetamine monoclonal antibody (mAb; K_D = 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 (AUC₀^{4.5 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 AUC₀^{4.5 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.

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