Clinical Pharmacology of Nicotine Enantiomers

摘要/摘要 最近，一些电子烟(EC)品牌声称使用的液体是 “无烟草”，意思是它们含有“合成”尼古丁。此类产品目前不受 符合FDA现有的烟草控制法规，并可能作为清洁剂销售给年轻人和其他人 而且比含有来自烟草的尼古丁的EC危害更小。电子烟制造商 可能会使用合成尼古丁作为避免FDA正在进行的ECs监管过程的一种方式。 尼古丁是一种具有一个不对称碳原子的手性化合物，可以作为两个镜像存在 左旋异构体或旋光异构体、左旋异构体(S)和右旋异构体 (R)-异构体。而烟草中的尼古丁几乎是独有的(S)-尼古丁，大多数合成尼古丁 由外消旋(S)-和(R)-尼古丁组成。动物研究表明(S)-尼古丁更多 比(R)-尼古丁更强的药理作用，但相对效力不同 效果差别很大。动物数据也发现了新陈代谢速率和途径的差异 两种尼古丁对映体。关于R的人体药理方面的信息很少 尼古丁或外消旋尼古丁。了解相对滥用的可能性、心血管影响 尼古丁对映体和它们的外消旋混合物的代谢差异对 FDA对合成尼古丁产品的适当监管。 我们建议使用稳定同位素方法学进行人类临床药理学研究。 比较S烟碱和(R)烟碱的药代动力学和药效学 外消旋尼古丁。我们将合成并准备人类给药的氚标记(S)- 和(R)-尼古丁。 在一项交叉研究中，有经验的EC用户将在三个不同的日期使用VAPE(S)、(R)-或外消旋 尼古丁既包括标准吸食(15支，每30秒一支)，也包括90分钟随意吸食 会议。结果指标将包括药代动力学、肺滞留、 尼古丁代谢、主观和心血管反应，以及尼古丁自我给药。 特别令人感兴趣的将是外消旋尼古丁混合物(如在许多合成尼古丁中发现的 产品)，(R)-尼古丁的存在影响(S)的药理和自我给药- 尼古丁。

Summary/Abstract Recently a number of electronic cigarettes (EC) brands have claimed to use liquids that are “tobacco-free”, meaning they contain “synthetic” nicotine. Such products are not currently subject to existing FDA tobacco control regulations and might be marketed to youth and others as cleaner and less harmful than EC that contain nicotine derived from tobacco. E-cigarette manufacturers may use synthetic nicotine as a way to avoid ongoing FDA regulatory processes for ECs. Nicotine is a chiral compound with one asymmetric carbon atom and can exist as two mirror image forms termed enantiomers or optical isomers, the levorotatory (S)-isomer and the dextrorotatory (R)-isomer. While nicotine from tobacco is almost exclusive (S)-nicotine, most synthetic nicotine is comprised of racemic (S)- and (R)- nicotine. Animal studies indicate that (S)- nicotine is more potent than (R)- nicotine for most pharmacological effects, but the relative potency for different effects varies considerably. Animal data also find differences in rates and pathways of metabolism of the two nicotine enantiomers. Very little information exists on the human pharmacology of R nicotine or racemic nicotine. Understanding the relative abuse potential, cardiovascular effects and metabolic differences of the nicotine enantiomers and their racemic mixture is important for appropriate FDA regulation of synthetic nicotine products. We propose to conduct a human clinical pharmacology study using stable isotope methodology to compare pharmacokinetics and pharmacodynamics of vaped (S)- and (R)- nicotine and racemic nicotine. We will synthesize and prepare for human administration deuterium labeled (S)- and (R)- nicotine. In a crossover study, experienced EC users will on three separate days vape (S)-, (R)- or racemic nicotine both in standardized sessions (15 puffs, one every 30 sec) and in a 90 min ad libitum use session. Outcome measures will include pharmacokinetics, pulmonary retention, patterns of nicotine metabolism, subjective and cardiovascular responses, and nicotine self-administration. Of particular interest will be how in racemic nicotine mixtures (as found in many synthetic nicotine products), the presence of (R)- nicotine affects the pharmacology and self-administration of (S)- nicotine.