Monoamine uptake inhibitors alter cocaine pharmacokinetics.
The time course of change in plasma levels of cocaine and its major metabolite benzoylecgonine following 3 mg/kg IV cocaine and the pharmacokinetic interaction between cocaine and several monoamine uptake inhibitors were investigated in conscious rats implanted with arterial and venous cannulae. The IV bolus administration of 3 mg/kg cocaine resulted in plasma levels of 1276 +/- 53 ng/ml cocaine at 0.5 min following its injection and the levels then rapidly declined to 768 +/- 110 ng/ml by 2 min. Thereafter, the decline of plasma cocaine levels was relatively slow. Plasma benzoylecgonine levels were similar at 0.5 and 2 min following cocaine injection but increased gradually over the next 25 min. Pretreatment with the norepinephrine-selective uptake inhibitors desipramine and nisoxetine, the serotonin-selective uptake inhibitor fluoxetine or the dopamine-selective uptake inhibitor GBR 12909 all enhanced plasma levels of cocaine after a 3 mg/kg IV bolus injection at 0.5, but not at 5 min after injection. The enhancement of plasma cocaine levels by GBR 12909 was of greater magnitude than that produced by desipramine, nisoxetine or fluoxetine. These agents, with the exception of the high dose (10 mg/kg) of GBR 12909, did not significantly alter plasma levels of benzoylecgonine measured at either 0.5 or 5 min following cocaine injection. These results indicate that monoamine uptake inhibitors can alter or interfere with the pharmacokinetics of cocaine and that this interaction is not due to a change in the biotransformation of cocaine. It is suggested that the central monoamine uptake sites serving as rapid distribution sites for cocaine may play a role in this pharmacokinetic interaction.
Tella
S R
SR
Department of Pharmacology, Georgetown University School of Medicine, Washington, DC.
Goldberg
S R
SR
D000818:Animals; D001711:Biotransformation; D003042:Cocaine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D003891:Desipramine / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000037:antagonists & inhibitors; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D018765:Dopamine Uptake Inhibitors; D014179:Neurotransmitter Uptake Inhibitors; D010879:Piperazines; D005473:Fluoxetine; C011386:nisoxetine; C005618:benzoylecgonine; C043425:vanoxerine; D003042:Cocaine; D003891:Desipramine; D009638:Norepinephrine