PT - JOURNAL ARTICLE AU - Elizabeth M. Laurenzana AU - Kelly A. Byrnes-Blake AU - Alessandra Milesi-Hallé AU - W. Brooks Gentry AU - D. Keith Williams AU - S. Michael Owens TI - USE OF ANTI-(+)-METHAMPHETAMINE MONOCLONAL ANTIBODY TO SIGNIFICANTLY ALTER (+)-METHAMPHETAMINE AND (+)-AMPHETAMINE DISPOSITION IN RATS AID - 10.1124/dmd.31.11.1320 DP - 2003 Nov 01 TA - Drug Metabolism and Disposition PG - 1320--1326 VI - 31 IP - 11 4099 - http://dmd.aspetjournals.org/content/31/11/1320.short 4100 - http://dmd.aspetjournals.org/content/31/11/1320.full SO - Drug Metab Dispos2003 Nov 01; 31 AB - 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. The American Society for Pharmacology and Experimental Therapeutics