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 in a genetically controlled in vitro animal model.


METHODS
Placentas from Sprague-Dawley rats were centrifuged, and microsomes were isolated. Four treatment groups were incubated with cocaine over four time periods: placental microsomes + cocaine, placental microsomes + diisopropyl fluorophosphate (an anticholinesterase) + cocaine, placental microsomes + cocaine + butyrylcholinesterase, and a blank (cocaine only). Gas chromatography was used to quantify cocaine (Limit of quantitation = 19 ng/ml) and metabolites. Gas chromatography/mass spectrometry was used to verify the identity of the metabolites.


RESULTS
Butyrylcholinesterase enhanced cocaine metabolism to ecgonine methyl ester. More than 40% of cocaine was metabolized to norcocaine by rat placental when diisopropyl fluorophosphate suppressed cocaine. Norcocaine is produced by hepatic N-demethylase action on methyl-bearing nitrogen in cocaine, suggesting that placenta and liver have this capacity. Gas chromatography/mass spectrometry was essential to the identification of norcocaine, because norcocaine is frequently not identified.


CONCLUSIONS
This biotransformation of cocaine to norcocaine may be a primary metabolic pathway induced in the cholinesterase-deficient placenta. This has clinical implications because norcocaine is ninefold more active physiologically than cocaine or ecgononine methylesterase.
Little
B B
BB
Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas 75235-9032, USA.
Roe
D A
DA
Stettler
R W
RW
Bohman
V R
VR
Westfall
K L
KL
Sobhi
S
S
D000818:Animals; D001711:Biotransformation; D002091:Butyrylcholinesterase / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000493:pharmacokinetics; D005260:Female; D007531:Isoflurophate / Q000494:pharmacology; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D008954:Models, Biological; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010920:Placenta / Q000201:enzymology* / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D007531:Isoflurophate; C008671:norcocaine; D010089:Oxidoreductases, N-Demethylating; D002091:Butyrylcholinesterase; D003042:Cocaine; C034524:ecgonine methyl ester