Metabolism of Cocaine by Cholinesterase During Pregnancy: Maternal and Fetal Activity

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Abstract
The objective of the present study was to analyze the metabolism of cocaine during pregnancy in vivo. Pregnant rats were injected with cocaine (25 mg/kg). Two treatment groups of 20 rats each were established. One group received cocaine only, and the other received cocaine plus anticholinesterase (X0.6 ud). Four animals per treatment group were sacrificed at five different time periods (0, 25, 45, 90, 135 min). Maternal blood was collected at sacrifice as were placentae and fetal tissues (brain, liver). Drug (cocaine and metabolites) concentrations were analyzed by dual capillary column gas chromatography (GC) fitted with FID and NPD detectors, and their identity verified by GC/mass spectrometry. We found that cocaine was metabolized differently in maternal and fetal compartments. Maternal metabolism was predominantly through the cholinesterase pathway. Fetal metabolism exhibited no evidence of cholinesterase activity with the predominant biotransformation of cocaine being through fetal liver n-demethylase because norcocaine was the primary metabolite detected in fetal tissues. Over time, norcocaine accumulated in the fetal brain more than any other organ. This effect was enhanced in the anticholinesterase treatment group, probably due to blunted maternal metabolism of the drug that resulted in more cocaine being transferred to the fetus. Norcocaine was a major fetal metabolite of cocaine. We hypothesize that fetal damage due to maternal cocaine exposure may be due in part to fetal metabolism of the drug to a physiologically more active metabolite, norcocaine. This effect was enhanced in the group that received anticholinesterase before cocaine was administered, implying a pharmacogenetic role in cocaine-associated fetal morbidity as result of maternal and placental metabolic activity.

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