Clinical Pharmacology of Nicotine Enantiomers

摘要/文摘

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.