PT  - JOURNAL ARTICLE
AU  - Lee Koetzner
AU  - James H. Woods
TI  - Characterization of Butyrylcholinesterase Antagonism of Cocaine-Induced Hyperactivity
AID  - 10.1124/dmd.30.6.716
DP  - 2002 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 716--723
VI  - 30
IP  - 6
4099  - http://dmd.aspetjournals.org/content/30/6/716.short
4100  - http://dmd.aspetjournals.org/content/30/6/716.full
SO  - Drug Metab Dispos2002 Jun 01; 30
AB  - Although there are several published demonstrations that exogenous butyrylcholinesterase (EC 3.1.1.8) works to antagonize cocaine in vivo, a systematic characterization of the enzyme-drug interaction is lacking as is confirmation of the mechanism of effect. This has been addressed using cocaine-induced locomotor activity in mice as a behavioral endpoint. The enzyme was effective, but the enzyme dose-antagonist effect relationship revealed an asymptotic partial maximum effect. This effect was not due to dose-dependent enzyme pharmacokinetics or to a stimulant effect of the cocaine metabolites but rather to partial metabolism of cocaine. Since neither metabolite of cocaine inhibited enzyme activity as potently as cocaine, partial metabolism is not likely due to end-product inhibition. The enzyme reduced the maximum effect of cocaine on locomotor activity. The mechanistic data are generally consistent: the enzyme was inactive against the nonester dopamine/norepinephrine uptake inhibitor, nomifensine, and a paraoxon-inactivated sample of enzyme was ineffective. However, the enzyme was effective against bupropion, a nonester dopamine uptake inhibitor. The American Society for Pharmacology and Experimental Therapeutics