Administration of purified human plasma cholinesterase protects against cocaine toxicity in mice

Background: Cocaine is metabolized in part by plasma cholinesterase to form ecgonine methyl ester. Decreased plasma cholinesterase activity is associated with enhanced cocaine toxicity in both humans and animals. This study was designed to determine whether the administration of exogenous plasma cholinesterase is protective against cocaine toxicity. Methods: Using a blinded protocol, female Swiss albino mice were randomized to receive an intraperitoneal injection of either 13.7 mg/kg of purified human plasma cholinesterase dissolved in phosphate buffered saline, or an equal volume of phosphate buffered saline as a control. One hour later, all animals received an intraperitoneal injection of either 100 or 125 mg/kg of cocaine, and the incidence of seizures and death was recorded. In a similar fashion, another group of animals was randomized to receive a human plasma cholinesterase dose of either 13.7 or 27.4 mg/kg, followed by 150 mg/kg of cocaine. Results: Administration of 13.7 mg/kg of human plasma cholinesterase increased plasma cholinesterase activity by a mean of 63 +/- 13 fold, with a T-max of 90 minutes and a V-d of 85 +/- 13 mL/kg. Cocaine's effects on seizures and death were attenuated by human plasma cholinesterase. A cocaine dose of 150 mg/kg represents an ED(100) for seizures and an LD(100). At this dose, lethality was reduced to 30% (p < 0.001) and seizures were reduced to 40% (p < 0.001) by administration of 27.4 mg/kg of human plasma cholinesterase. Conclusions: Pretreatment with purified human plasma cholinesterase protects mice against the convulsive and lethal effects of cocaine.