A NEW PLACENTAL ENZYME IN THE METABOLISM OF COCAINE - AN IN-VITRO ANIMAL-MODEL

OBJECTIVE: The aim of this study was to analyze placental metabolism i n a genetically controlled in vitro animal model. STUDY DESIGN: Placen tas from Sprague-Dawley rats were centrifuged, and microsomes were iso lated. Four treatment groups were incubated with cocaine over four tim e periods: placental microsomes + cocaine, placental microsomes + diis opropyl fluorophosphate (an anticholinesterase) + cocaine, placental m icrosomes + cocaine + butyrylcholinesterase, and a blank (cocaine only ). Gas chromatography was used to quantify cocaine (Limit of quantitat ion = 19 ng/ml) and metabolites. Gas chromatography/mass spectrometry was used to verify the identity of the metabolites. RESULTS: Butyrylch olinesterase enhanced cocaine metabolism to ecgonine methyl ester. Mor e than 40% of cocaine was metabolized to norcocaine by rat placenta wh en diisopropyl fluorophosphate suppressed cocaine. Norcocaine is produ ced by hepatic N-demethylase action on methyl-bearing nitrogen in coca ine, suggesting that placenta and liver have this capacity. Gas chroma tography/mass spectrometry was essential to the identification of norc ocaine, because norcocaine is frequently not identified. CONCLUSIONS: This biotransformation of cocaine to norcocaine may be a primary metab olic pathway induced in the cholinesterase-deficient placenta. This ha s clinical implications because norcocaine is ninefold more active phy siologically than cocaine or ecgononine methylesterase.