Effects of cigarette smoking and carbon monoxide on chlorzoxazone and caffeine metabolism.
OBJECTIVE
Our objectives were to examine the effects of cigarette smoking on the disposition kinetics of chlorzoxazone and caffeine as probes of cytochrome p450 (CYP) 2E1, CYP1A2, xanthine oxidase, and N-acetyltransferase-2 activity and to test the hypothesis that carbon monoxide inhibits drug metabolism via these pathways.


METHODS
Twelve cigarette smokers were studied in 3 treatment conditions, each lasting 7 days, during which they smoked cigarettes, breathed carbon monoxide to achieve carboxyhemoglobin levels similar to those associated with cigarette smoking, or breathed air. In each treatment condition, subjects received oral chlorzoxazone (250 mg) and caffeine (250 mg) with measurement of disposition kinetics and urine metabolite profiles.


RESULTS
Compared with the air condition, cigarette smoking significantly induced the metabolism of chlorzoxazone (oral clearance, 5.9 +/- 1.5 mL x min(-1) x kg(-1) versus 4.8 +/- 1.0 mL x min(-1) x kg(-1), P <.005) and caffeine (2.0 +/- 0.8 mL x min(-1) x kg(-1) versus 1.5 +/- 0.7 mL x min(-1) x kg(-1), P <.001) but had no effect on caffeine urine metabolite ratios that reflect xanthine oxidase and N-acetyltransferase-2 activity. Considerable individual variability was noted in the extent of induction of metabolism by cigarette smoking, particularly as it affects chlorzoxazone (change in oral clearance ranged from -10% to +71%). Carbon monoxide had no effect on chlorzoxazone or caffeine metabolism or caffeine metabolic profile.


CONCLUSIONS
This study provides novel evidence that cigarette smoking accelerates chlorzoxazone metabolism, most likely reflecting induction of CYP2E1 activity, in humans. Induction of CYP2E1 activity by cigarette smoking could contribute to tobacco-induced cancer, alcohol-induced liver disease, and the risk of acetaminophen hepatotoxicity.
Benowitz
Neal L
NL
Division of Clinical Pharmacology and Experimental Therapeutics, San Francisco General Hospital Medical Center, University of California, San Francisco, CA 94143-1220, USA. nbeno@itsa.ucsf.edu
Peng
Margaret
M
Jacob
Peyton
P
D000328:Adult; D026924:Amino Acid Transport System A; D026905:Amino Acid Transport Systems; D019540:Area Under Curve; D002110:Caffeine / Q000493:pharmacokinetics*; D002248:Carbon Monoxide / Q000097:blood*; D002263:Carboxyhemoglobin / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics*; D002753:Chlorzoxazone / Q000493:pharmacokinetics*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009125:Muscle Relaxants, Central / Q000493:pharmacokinetics*; D012907:Smoking / Q000097:blood / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000378:metabolism
D026924:Amino Acid Transport System A; D026905:Amino Acid Transport Systems; D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; D009125:Muscle Relaxants, Central; C432411:Slc38a1 protein, mouse; D002110:Caffeine; D002248:Carbon Monoxide; D002263:Carboxyhemoglobin; D019392:Cytochrome P-450 CYP2E1; D019388:Cytochrome P-450 CYP1A2; D014969:Xanthine Oxidase; D002753:Chlorzoxazone