Carbamazepine but not valproate induces CYP2A6 activity in smokers with mental illness.
BACKGROUND
Antiepileptic drugs (AED) are being increasingly used in the management of serious mental illness, but their effects on nicotine metabolism have not been studied.


METHODS
This study investigated the effects of three AEDs (carbamazepine, oxcarbazepine, and valproic acid) on nicotine and nicotine metabolite levels in 149 smokers with schizophrenia and bipolar disorder who participated in an afternoon blood draw for nicotine, cotinine, and 3'-hydroxycotinine (3HC). The ratio of 3HC to cotinine was calculated as a marker of CYP2A6 metabolic activity. Among the participants, 8 smokers were taking carbamazepine, 6 were taking oxcarbazepine, and 40 were taking valproic acid.


RESULTS
The 3HC/cotinine ratio was significantly higher in individuals taking carbamazepine or oxcarbazepine (combined, n = 14) versus those not taking either (mean 0.993 versus 0.503; P < 0.001). The cotinine/cigarette per day ratio was significantly lower in individuals taking carbamazepine or oxcarbazepine. The 3HC/cotinine ratios were also significantly higher in the subgroup of individuals taking carbamazepine (n = 8) versus those not taking it. There were no significant differences in nicotine or cotinine levels or 3HC/cotinine ratios in individuals taking valproic acid versus those not taking it. We conducted backward stepwise linear regression models to identify predictors of the log transformed 3HC/cotinine ratios. Taking carbamazepine and number of cigarettes smoked per day were significant determinants of log 3HC/cotinine.


CONCLUSIONS
Carbamazepine likely induces hepatic metabolism via CYP2A6 and is associated with increased 3HC/cotinine ratios.


CONCLUSIONS
Increased nicotine metabolism in individuals using AED has implications for increased smoking behavior and exposure to more tobacco toxins, which warrants further study.
Williams
Jill M
JM
UMDNJ-Robert Wood Johnson Medical School, 317 George Street, Suite 105, New Brunswick, NJ 08901-2008, USA. jill.williams@umdnj.edu
Gandhi
Kunal K
KK
Benowitz
Neal L
NL
D000328:Adult; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000378:metabolism; D001714:Bipolar Disorder / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology*; D002220:Carbamazepine / Q000031:analogs & derivatives / Q000494:pharmacology; D003367:Cotinine / Q000031:analogs & derivatives / Q000097:blood; D065637:Cytochrome P-450 CYP2A6; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000097:blood; D000078330:Oxcarbazepine; D012559:Schizophrenia / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology*; D012907:Smoking / Q000097:blood* / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology; D055815:Young Adult
D000927:Anticonvulsants; C001381:hydroxycotinine; D002220:Carbamazepine; D014635:Valproic Acid; D009538:Nicotine; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D003367:Cotinine; D000078330:Oxcarbazepine