Use of anti-(+)-methamphetamine monoclonal antibody to significantly alter (+)-methamphetamine and (+)-amphetamine disposition in rats.
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 approximately 5% in controls to approximately 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 approximately 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.
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 611, Little Rock, AR 72205, USA. laurenzanaelizabeth@uams.edu
Elizabeth M
EM
Laurenzana
Kelly A
KA
Byrnes-Blake
Alessandra
A
Milesi-Hallé
W Brooks
WB
Gentry
D Keith
DK
Williams
S Michael
SM
Owens
D000661:Amphetamine / Q000493:pharmacokinetics*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D008297:Male; D008694:Methamphetamine / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
D000911:Antibodies, Monoclonal; D008694:Methamphetamine; D000661:Amphetamine