Benowitz N L, Zevin S, Jacob P
Division of Clinical Pharmacology and Experimental Therapeutics, San Francisco General Hospital Medical Center, California 94110, USA.
Br J Clin Pharmacol. 1997 Mar;43(3):259-67. doi: 10.1111/j.1365-2125.1997.00566.x.
Nicotine nasal spray and transdermal nicotine are effective aids to smoking cessation, and are being evaluated for treatment of other medical diseases. Wide variation in levels of nicotine and its metabolite, cotinine, have been observed with such therapies. This study aimed primarily to assess sources of individual variability in nicotine and metabolite plasma levels from these dosing systems and from cigarette smoking.
Twelve cigarette smokers, studied on a clinical research ward, received four treatments of 5 days duration each, including (1) cigarette smoking, 16 cigarettes/day; (2) transdermal nicotine, 15 mg/day; (3) nicotine nasal spray, 24-1 mg doses/day; (4) placebo nicotine nasal spray, 24 doses/day. On a different occasion, the disposition kinetics of nicotine and cotinine were determined via infusion of deuterium-labeled nicotine and continine. Plasma levels of nicotine, cotinine, and 3'-hydroxycotinine and daily intake of nicotine during various treatments were examined, as well as pharmacokinetic factors that determined plasma nicotine and continine levels.
There was considerable individual variation in plasma nicotine and cotinine levels and in the daily of nicotine absorbed from various delivery systems, with most variability with nicotine nasal spray (fivefold) and least for transdermal nicotine (two-to threefold). Plasma nicotine levels were determined most strongly by nicotine clearance. Continine levels were determined most strongly by dose of nicotine and, to a lesser extent, the clearance of cotinine and fractional conversion of nicotine to continine.
Plasma levels of nicotine and cotinine produced by nicotine therapies are highly variable, due to both wide variability in individual pharmacokinetics and in dose delivery from the products. To compensate for individual differences in clearance, individualization of nicotine dosing based on therapeutic drug monitoring with comparison to nicotine or continine levels during cigarette smoking prior to treatment may be necessary to optimize nicotine therapy. This study also validates a recently proposed method for estimating absolute bioavailability of a drug using drug and metabolite pharmacokinetic data, and presents novel data on plasma levels of the metabolite trans-3'-hydroxycotinine in people.
尼古丁鼻喷雾剂和经皮尼古丁是有效的戒烟辅助手段，目前正在评估其对其他医学疾病的治疗效果。使用这些疗法时，已观察到尼古丁及其代谢物可替宁的水平存在很大差异。本研究主要旨在评估这些给药系统以及吸烟导致的尼古丁和代谢物血浆水平个体差异的来源。
12名吸烟者在临床研究病房接受了四种为期5天的治疗，包括：（1）吸烟，每天16支；（2）经皮尼古丁，每天15毫克；（3）尼古丁鼻喷雾剂，每天24 - 1毫克剂量；（4）安慰剂尼古丁鼻喷雾剂，每天24剂。在另一个时间段，通过输注氘标记的尼古丁和可替宁来确定尼古丁和可替宁的处置动力学。检测了各种治疗期间尼古丁、可替宁和3'-羟基可替宁的血浆水平以及尼古丁的每日摄入量，以及决定血浆尼古丁和可替宁水平的药代动力学因素。
血浆尼古丁和可替宁水平以及从各种给药系统吸收的尼古丁每日摄入量存在相当大的个体差异，其中尼古丁鼻喷雾剂的差异最大（五倍），经皮尼古丁的差异最小（两到三倍）。血浆尼古丁水平主要由尼古丁清除率决定。可替宁水平主要由尼古丁剂量决定，在较小程度上由可替宁清除率和尼古丁向可替宁的分数转化率决定。
尼古丁疗法产生的血浆尼古丁和可替宁水平高度可变，这是由于个体药代动力学和产品剂量递送的广泛差异所致。为了补偿清除率的个体差异，基于治疗药物监测并与治疗前吸烟期间的尼古丁或可替宁水平进行比较来个体化尼古丁给药，可能是优化尼古丁疗法所必需的。本研究还验证了一种最近提出的使用药物和代谢物药代动力学数据估计药物绝对生物利用度的方法，并提供了关于人体中代谢物反式-3'-羟基可替宁血浆水平的新数据。
