In vitro hepatic biotransformation of cocaine in maternal and fetal guinea pigs. Induction of cocaine N-demethylation with cocaine pretreatment.
In vitro N-demethylation of cocaine (COC) was examined in five saline (SAL) and five COC-treated pregnant guinea pigs and their fetuses (60 days, term 69 days). Microsomes from maternal and fetal guinea pigs produced norcocaine (NOR), benzoylnorecgonine (BN), and benzoylecgonine (BE) when incubated with COC. The initial rate of NOR formation was (mean +/- SE) 0.69 +/- 0.09 and 0.002 +/- 0.002 nmol/min/mg in microsomes from SAL-treated dams and their fetuses, respectively. The minimal fetal N-demethylation suggests BN seen previously in vivo after chronic maternal COC administration resulted from maternal formation of NOR and subsequent maternal or fetal hydrolysis to BN. COC pretreatment increased the initial rate of NOR formation to 1.38 +/- 0.28 nmol/min/mg (p < 0.05) and increased the extent of NOR formation by 12 min (p < 0.05). There was no change in total cytochrome P-450 concentrations in the dams. COC pretreatment had no effect on fetal hepatic N-demethylation of COC or total cytochrome P-450 content. The rate of NOR production plateaued in microsomes from both treatment groups by 20 min of incubation and could be restored when the microsomes were washed, repelleted, and reincubated. This suggests a soluble metabolite of COC inhibits COC N-demethylation. Microsomes from both SAL- and COC-treated animals produced this factor in the presence of COC, but the enzyme(s) responsible for COC N-demethylation in the SAL-treated pregnant guinea pig were more sensitive to inhibition than COC-pretreated animals.
Sandberg
J A
JA
Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Portland, OR.
Murphey
L J
LJ
Olsen
G D
GD
D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003640:Dealkylation; D005260:Female; D005333:Fetus / Q000378:metabolism*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy
D000632:Aminopyrine; C008671:norcocaine; C005618:benzoylecgonine; D003577:Cytochrome P-450 Enzyme System; D003042:Cocaine; C012209:benzoylnorecgonine