Pharmacodynamic mechanisms of monoclonal antibody-based antagonism of (+)-methamphetamine in rats.
Our studies examined pharmacokinetic mechanisms involved in high-affinity (K(d) approximately 11 nM) monoclonal antibody-based antagonism of (+)-methamphetamine-induced locomotor effects. Male rats received (+)-methamphetamine (0.3, 1, or 3 mg/kg i.v.) followed 30 min later by saline or anti-(+)-methamphetamine monoclonal antibody. All groups received a constant dose of monoclonal antibody that was equimolar in binding sites to the body burden of a 1 mg/kg i.v. (+)-methamphetamine dose 30 min after administration. The monoclonal antibody antagonized locomotor effects due to 0.3 and 1 mg/kg (+)-methamphetamine. In contrast, monoclonal antibody treatment increased locomotor activity due to 3 mg/kg (+)-methamphetamine. We also investigated the serum and brain pharmacokinetics of (+)-methamphetamine without and with the monoclonal antibody. Rats received (+)-methamphetamine (1 mg/kg i.v.) followed by saline or monoclonal antibody treatment at 30 min. The monoclonal antibody significantly increased serum methamphetamine concentrations and significantly decreased brain methamphetamine concentrations. These data indicate that anti-(+)-methamphetamine monoclonal antibody-induced pharmacodynamics are complex, but are related to time-dependent changes in (+)-methamphetamine brain distribution.
Byrnes-Blake
Kelly A
KA
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 611, Little Rock, AR 72205, USA.
Laurenzana
Elizabeth M
EM
Carroll
F Ivy
FI
Abraham
Philip
P
Gentry
W Brooks
WB
Landes
Reid D
RD
Owens
S Michael
SM
D000661:Amphetamine / Q000097:blood / Q000493:pharmacokinetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology; D000918:Antibody Specificity; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D008297:Male; D008694:Methamphetamine / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D000697:Central Nervous System Stimulants; D008694:Methamphetamine; D000661:Amphetamine