Genetic and pharmacokinetic determinants of response to transdermal nicotine in white, black, and Asian nonsmokers.
The aim of the study was to examine genetic, pharmacokinetic, and demographic factors that influence sensitivity to nicotine in never-smokers. Sixty never-smokers, balanced for gender and race (white, black, and Asian), wore 7-mg nicotine skin patches for up to 8 h. Serial plasma nicotine concentrations and subjective and cardiovascular effects were measured, and genetic variation in the CYP2A6 gene, encoding the primary enzyme responsible for nicotine metabolism, was assessed. Nicotine toxicity requiring patch removal developed in nine subjects and was strongly associated with rate of increase and peak concentrations of plasma nicotine. Toxicity and subjective and cardiovascular effects of nicotine were associated with the presence of reduced-function CYP2A6 alleles, presumably reflecting slow nicotine metabolic inactivation. This study has implications for understanding individual differences in responses to nicotine medications, particularly when they are used for treating medical conditions in nonsmokers, and possibly in vulnerability to developing nicotine dependence.
1] Division of Clinical Pharmacology and Experimental Therapeutics, Medical Service, San Francisco General Hospital Medical Center, University of California, San Francisco, San Francisco, California, USA [2] Department of Pediatrics, San Francisco General Hospital Medical Center, University of California San Francisco, San Francisco, California, USA.
D A
DA
Dempsey
G
G
St Helen
P
P
Jacob
R F
RF
Tyndale
N L
NL
Benowitz
D000279:Administration, Cutaneous; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D044466:Asian People; D044383:Black People; D065637:Cytochrome P-450 CYP2A6; D005260:Female; D006801:Humans; D008297:Male; D009538:Nicotine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D061485:Tobacco Use Cessation Devices / Q000009:adverse effects; D014029:Tobacco Use Disorder / Q000201:enzymology / Q000208:ethnology* / Q000235:genetics*; D044465:White People; D055815:Young Adult
D009538:Nicotine; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6