MONOAMINE UPTAKE INHIBITORS ALTER COCAINE PHARMACOKINETICS

The time course of change in plasma levels of cocaine and its major me tabolite benzoylecgonine following 3 mg/kg IV cocaine and the pharmaco kinetic interaction between cocaine and several monoamine uptake inhib itors were investigated in conscious rats implanted with arterial and venous cannulae. The IV bolus administration of 3 mg/kg cocaine result ed 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/m l by 2 min. Thereafter, the decline of plasma cocaine levels was relat ively slow. Plasma benzoylecgonine levels were similar at 0.5 and 2 mi n following cocaine injection but increased gradually over the next 25 min. Pretreatment with the norepinephrine-selective ve uptake inhibit ors desipramine and nisoxetine, the serotonin-selective uptake inhibit or 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 co caine levels by GBR 12909 was of greater magnitude than that produced by desipramine, nisoxetine or fluoxetine. These agents, with the excep tion of the high dose (10 mg/kg) of GBR 12909, did not significantly a lter plasma levels of benzoylecgonine measured at either 0.5 or 5 min following cocaine injection. These results indicate that monoamine upt ake inhibitors can alter or interfere with the pharmacokinetics of coc aine and that this interaction is not due to a change in the biotransf ormation 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.