Benowitz N L, Jacob P
Clinical Pharmacology Unit, San Francisco General Hospital Medical Center, CA 94110.
Clin Pharmacol Ther. 1994 Nov;56(5):483-93. doi: 10.1038/clpt.1994.169.
(1) To determine the disposition kinetics of nicotine and cotinine, including the fractional conversion of nicotine to cotinine, (2) to compare the disposition kinetics of deuterium-labeled and unlabeled cotinine, and (3) to develop a pharmacokinetically based method for estimating daily intake of nicotine from cigarette smoking.
Twenty cigarette smokers received a combined infusion of deuterium-labeled nicotine (d2) and cotinine (d4). Six nonsmokers received a combined infusion of unlabeled cotinine, cotinine-d2 and cotinine-d4. Daily intake of nicotine was estimated with use of the plasma cotinine concentration during ad libitum smoking, clearance of labeled cotinine, and fractional conversion of nicotine to cotinine.
The kinetics of labeled versus unlabeled cotinine and of cotinine in smokers versus nonsmokers were similar. On average, 72% of nicotine was converted to cotinine, with a range from 55% to 92%. Subjects with lower clearances of nicotine had lower fractional conversion of nicotine to cotinine, indicating that this is the most rapid of the proximate metabolic pathways for nicotine. The equation for estimating daily intake of nicotine from smoking was: Dnic (mg/24 hr) = K x (Plasma Cot) (ng/ml), where K averaged 0.08, with a range from 0.047 to 0.102. Individual variability in the clearance of cotinine (coefficient of variation, 27.5%) accounts for more of the variability in K than does variability in the fractional conversion of nicotine to cotinine (coefficient of variation, 12.3%).
Our study provides quantitative data on individual variability in the extent of C-oxidation of nicotine to cotinine and a quantitative perspective on the use of plasma cotinine as an indicator of daily intake of nicotine from tobacco.
（1）确定尼古丁和可替宁的处置动力学，包括尼古丁向可替宁的转化分数；（2）比较氘标记和未标记可替宁的处置动力学；（3）开发一种基于药代动力学的方法来估算吸烟导致的尼古丁日摄入量。
20名吸烟者接受了氘标记尼古丁（d2）和可替宁（d4）的联合输注。6名非吸烟者接受了未标记可替宁、可替宁 - d2和可替宁 - d4的联合输注。通过随意吸烟期间的血浆可替宁浓度、标记可替宁的清除率以及尼古丁向可替宁的转化分数来估算尼古丁日摄入量。
标记与未标记可替宁的动力学以及吸烟者与非吸烟者体内可替宁的动力学相似。平均而言，72%的尼古丁转化为可替宁，范围为55%至92%。尼古丁清除率较低的受试者，其尼古丁向可替宁的转化分数也较低，这表明这是尼古丁最快速的近端代谢途径。估算吸烟导致的尼古丁日摄入量的公式为：Dnic（mg/24小时）= K ×（血浆可替宁浓度）（ng/ml），其中K的平均值为0.08，范围为0.047至0.102。可替宁清除率的个体差异（变异系数为27.5%）比尼古丁向可替宁转化分数的差异（变异系数为12.3%）在K的变异中占比更大。
我们的研究提供了关于尼古丁C - 氧化为可替宁程度的个体差异定量数据，以及关于使用血浆可替宁作为烟草中尼古丁日摄入量指标的定量观点。
