Lerman Caryn, Tyndale Rachel, Patterson Freda, Wileyto E Paul, Shields Peter G, Pinto Angela, Benowitz Neal
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
Clin Pharmacol Ther. 2006 Jun;79(6):600-8. doi: 10.1016/j.clpt.2006.02.006. Epub 2006 May 11.
Nicotine is metabolized to cotinine, and cotinine is metabolized to 3'-hydroxycotinine (3-HC) by the liver enzyme cytochrome P450 (CYP) 2A6. More rapid metabolism of nicotine may result in lower nicotine blood levels from nicotine replacement products and poorer smoking cessation outcomes. This study evaluated the utility of the 3-HC/cotinine ratio as a predictor of the efficacy of nicotine replacement therapy as an aid for smoking cessation.
By use of an open-label design, 480 treatment-seeking smokers were randomly assigned to 8 weeks of transdermal nicotine or nicotine nasal spray use, plus behavioral group counseling. Assessments included demographics, smoking history, body mass index, and plasma nicotine, cotinine, and 3-HC concentrations, as well as CYP2A6 genotypes. Smoking cessation was biochemically verified at the end of treatment and at 6-month follow-up.
The rate of nicotine metabolism, as indicated by pretreatment 3-HC/cotinine ratio derived from cigarette smoking, predicted the effectiveness of transdermal nicotine at both time points. The odds of abstinence were reduced by almost 30% with each increasing quartile of metabolite ratio (odds ratio, 0.72 [95% confidence interval, 0.57-0.90]; P=.005). Higher metabolite ratios also predicted lower nicotine concentrations (beta=-1.72, t(179)=-3.31, P<.001), as well as more severe cravings for cigarettes after 1 week of treatment (beta=0.32, t(190)=2.91, P=.004). The metabolite ratio did not predict cessation with use of nicotine nasal spray (odds ratio, 1.05 [95% confidence interval, 0.83-1.33]; P=.68).
The nicotine metabolite ratio might be useful in screening smokers to determine likely success with a standard dose of transdermal nicotine.
尼古丁代谢生成可替宁，可替宁经肝脏细胞色素P450（CYP）2A6酶代谢为3'-羟基可替宁（3-HC）。尼古丁代谢更快可能导致尼古丁替代产品的尼古丁血药浓度降低，戒烟效果更差。本研究评估了3-HC/可替宁比值作为尼古丁替代疗法辅助戒烟疗效预测指标的效用。
采用开放标签设计，将480名寻求治疗的吸烟者随机分配接受8周的经皮尼古丁或尼古丁鼻喷雾剂治疗，外加行为团体咨询。评估内容包括人口统计学特征、吸烟史、体重指数以及血浆尼古丁、可替宁和3-HC浓度，还有CYP2A6基因型。在治疗结束时和6个月随访时通过生化方法验证戒烟情况。
吸烟产生的治疗前3-HC/可替宁比值所表明的尼古丁代谢率，在两个时间点均能预测经皮尼古丁的疗效。代谢物比值每增加一个四分位数，戒烟几率降低近30%（比值比，0.72[95%置信区间，0.57 - 0.90]；P = 0.005）。较高的代谢物比值还预示着较低的尼古丁浓度（β = -1.72，t(179) = -3.31，P < 0.001），以及治疗1周后对香烟的更强烈渴望（β = 0.32，t(190) = 2.91，P = 0.004）。代谢物比值不能预测使用尼古丁鼻喷雾剂的戒烟情况（比值比，1.05[95%置信区间，0.83 - 1.33]；P = 0.68）。
尼古丁代谢物比值可能有助于筛选吸烟者，以确定标准剂量经皮尼古丁治疗可能取得的成功。
