Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity
Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity
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DOI：
10.1016/j.clpt.2004.02.011
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发表时间：
2004-07-01
影响因子：
6.7
通讯作者：
Benowitz, NL
中科院分区：
文献类型：
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作者：
Dempsey, D;Tutka, P;Benowitz, NL
背景：尼古丁以及多种其他药物和毒素由细胞色素P450（CYP）2A6代谢。我们的目的是评估口服尼古丁并通过测定反式 - 3' - 羟基可替宁（3HC）/可替宁（COT）代谢物比率，作为细胞色素P450 2A6活性的一种非侵入性探针。
方法：62名健康志愿者接受了氘标记尼古丁（2毫克）及其代谢物可替宁（10毫克）的口服溶液。随时间测定血浆尼古丁以及血浆和唾液中可替宁及3HC的浓度。
结果：从氘标记可替宁得出的3HC/COT比率，无论是在血浆中（给药后2 - 8小时）还是在唾液中（6小时）测定，都与尼古丁的口服清除率密切相关（r = 0.76 - 0.83，取决于测量时间）。14名吸烟者从烟草中获取的尼古丁在6小时的3HC/COT比率与从氘标记尼古丁得出的比率高度相关（r = 0.88），并且也与尼古丁的口服清除率高度相关（r = 0.90）。两名具有无活性CYP2A6等位基因纯合子的受试者未产生3HC，证实了代谢物比率的特异性。3HC/COT比率也与可替宁的清除率和半衰期高度相关，这与可替宁也主要由CYP2A6代谢的事实相符。
结论：从作为探针药物给予的尼古丁或从烟草使用中获取的尼古丁得出的3HC/COT比率，无论是在血浆还是唾液中测定，都与尼古丁的口服清除率高度相关。该比率似乎是尼古丁代谢速率的一种有用的非侵入性标志物（这在研究尼古丁成瘾和吸烟行为方面很重要），也是CYP2A6活性的一种通用标志物（这在研究药物和毒素代谢方面很重要）。
Background: Nicotine and a variety of other drugs and toxins are metabolized by cytochrome P450 (CYP) 2A6. Our objective was to evaluate the use of oral nicotine with measurement of the trans-3'-hydroxycotinine (3HC)/cotinine (COT) metabolite ratio as a noninvasive probe of CYP2A6 activity.Methods. Sixty-two healthy volunteers received an oral solution of deuterium-labeled nicotine (2 mg) and its metabolite cotinine (10 mg). Plasma nicotine and plasma and saliva cotinine and 3HC concentrations were measured over time.Results. The 3HC/COT ratio derived from deuterium-labeled cotinine, measured in either plasma (2-8 hours after administration) or saliva (at 6 hours), was strongly correlated with the oral clearance of nicotine (r = 0.76-0.83, depending on the time of measurement). The 6-hour 3HC/COT ratio from nicotine derived from tobacco in 14 smokers was highly correlated with the ratio derived from deuterium-labeled nicotine (r = 0.88) and was also highly correlated with the oral clearance of nicotine (r = 0.90). Two subjects homozygous for inactive CYP2A6 alleles produced no 3HC, confirming the specificity of the metabolite ratio. The 3HC/COT ratio was also highly correlated with the clearance and half-life of cotinine, consistent with the fact that cotinine is also primarily metabolized by CYP2A6.Conclusions: The 3HC/COT ratio derived from nicotine either administered as a probe drug or from tobacco use, measured in either plasma or saliva, is highly correlated with the oral clearance of nicotine. The ratio appears to be a useful noninvasive marker of the rate of nicotine metabolism (which is important in studying nicotine addiction and smoking behavior), as well as a general marker of CYP2A6 activity (which is important in studying drug and toxin metabolism).