School of Biomedical Sciences, Faculty of Health Sciences, The University of Sydney

Abstract:

Cocaine is one of the main alkaloids of Erythroxylum coca that has a long history of human use and abuse. Cocaine acts as a local anaesthetic and stimulant causing increased alertness and a sense of euphoria. Sustained abuse of cocaine as a recreational drug is widespread around the world. Cocaine abuse during pregnancy is of major concern in certain countries where pregnant women take several drugs along with cocaine because it is known that cocaine can cross placenta. Cocaine has been reported to cause toxicity mainly to cardiovascular system and to a lesser extent to the liver. Cocaine is extensively metabolised in humans so that only a small percentage is excreted unaltered in urine. Cocaine is metabolized in vivo to pharmacologically inactive metabolites ecgonine methyl ester (ECG), benzoylecgonine (BE) and ecgonine (ECG). Among the metabolites BE has six times longer half-life than cocaine. Norcocaine is a relatively minor metabolite in humans. Molecular modelling analyses show that among cocaine and its metabolites, the metabolite cocaine N-oxide has the lowest LUMO-HOMO energy difference indicating that it has the greatest kinetic lability. The surface of the metabolite is also found to abound in electron-deficient regions so that it can cause oxidation of reduced form of glutathione and that of nucleobases in DNA, thus compromising the antioxidant status of the cell and inducing damage to DNA.

Key words: cocaine, norcocaine, ecgonine, cocaethylene, molecular modelling

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