Abstract
In primates, nicotine is metabolically inactivated in the liver by CYP2A6 and possibly CYP2B6. Changes in the levels of these two enzymes may affect nicotine pharmacokinetics and influence smoking behaviors. This study investigated the independent and combined effects of ethanol self-administration and nicotine treatment (0.5 mg/kg b.i.d. s.c.) on hepatic CYP2A6 and CYP2B6 levels (mRNA, protein, and enzymatic activity), in vitro nicotine metabolism, and in vivo nicotine pharmacokinetics in monkeys. CYP2A6 mRNA and protein levels and in vitro coumarin (selective CYP2A6 substrate) and nicotine metabolism were decreased by nicotine treatment but unaffected by ethanol. CYP2B6 protein levels and in vitro bupropion (selective CYP2B6 substrate) metabolism were increased by ethanol but unaffected by nicotine treatment; CYP2B6 mRNA levels were unaltered by either treatment. Combined ethanol and nicotine exposure decreased CYP2A6 mRNA and protein levels, as well as in vitro coumarin and nicotine metabolism, and increased CYP2B6 protein levels and in vitro bupropion metabolism, with no change in CYP2B6 mRNA levels. Chronic nicotine resulted in higher nicotine plasma levels achieved after nicotine administration, consistent with decreased CYP2A6. Ethanol alone, or combined with nicotine, resulted in lower nicotine plasma levels by a mechanism independent of the change in these enzymes. Thus, nicotine can decrease hepatic CYP2A6, reducing the metabolism of its substrates, including nicotine, whereas ethanol can increase hepatic CYP2B6, increasing the metabolism of CYP2B6 substrates. In vivo nicotine pharmacokinetics are differentially affected by ethanol and nicotine, but when both drugs are used in combination the effect more closely resembles ethanol alone.
Footnotes
This study was supported by the Centre for Addiction and Mental Health; the Canadian Institute of Health Research [Grant MOP97751]; the Canadian Foundation for Innovation [Grants 20289, 16014]; the Ontario Ministry of Research and Innovation; the Canada Research Chair in Pharmacogenetic (R.F.T.); and the Canadian Liver Foundation and Scholarship Program for Interdisciplinary Capacity Enhancement.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
- AGM
- African green monkey
- ANOVA
- analysis of variance
- AUC
- area under the time curve
- AUC0–6h
- AUC from 0 to 6 h
- AUC0-∞
- AUC from 0 to infinity
- Cmax
- maximal concentration of nicotine
- HPLC
- high-performance liquid chromatography
- NCO
- nicotine C-oxidation
- PCR
- polymerase chain reaction
- PK
- pharmacokinetics
- TBS
- Tris-buffered saline
- Vd
- volume of distribution.
- Received July 18, 2012.
- Accepted August 29, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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