Ghosheh O A, Dwoskin L P, Miller D K, Crooks P A
College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.
Drug Metab Dispos. 2001 May;29(5):645-51.
Concentrations of nicotine, cotinine, and nornicotine in brain and blood following both intermittent and continuous administration of [2'-(14)C]nicotine to rats were determined to assess nicotine metabolite accumulation in brain following repeated nicotine administration. For intermittent studies, rats were administered s.c. 1 to 10 doses of nicotine (0.3 mg/kg, 15 or 25 microCi of [2'-(14)C]nicotine; 30-min interinjection interval). For continuous administration studies, rats were implanted s.c. with an osmotic minipump delivering nicotine (0.8 mg/kg/day, 25 or 50 microCi of [2'-(14)C]nicotine for 1-21 days). Whole brain and trunk blood was collected. The concentration of [2'-(14)C]nicotine and its metabolites was determined via high-pressure liquid radiochromatography. Brain concentrations of nicotine, cotinine, and nornicotine increased 2-, 12-, and 9-fold, respectively, following 10 injections, reaching a plateau following the fifth injection. Brain blood ratios indicate an enhanced preferential distribution of nornicotine to brain with increasing numbers of injections. Across the 21-day period of continuous infusion, blood nicotine and nornicotine concentrations remained relatively constant, whereas concentrations in brain increased approximately 4-fold. Generally, cotinine concentrations in brain and blood did not change across the infusion period. Brain/blood ratios indicate an increase in nicotine distribution into brain across days of nicotine infusion. Results demonstrate that both nicotine and its metabolites accumulate in brain following repeated nicotine administration, and indicate that brain nicotine concentration can not be extrapolated from plasma cotinine or nicotine concentrations. Thus, nornicotine accumulation following repeated nicotine administration suggests that this metabolite plays a contributory role in the neuropharmacological effects of nicotine.
为评估重复给予尼古丁后尼古丁代谢产物在脑中的蓄积情况，测定了对大鼠间歇性和持续性给予[2'-(14)C]尼古丁后，脑和血液中尼古丁、可替宁和去甲烟碱的浓度。在间歇性研究中，给大鼠皮下注射1至10剂尼古丁（0.3mg/kg，含15或25μCi的[2'-(14)C]尼古丁；注射间隔30分钟）。在持续性给药研究中，给大鼠皮下植入渗透微型泵，以输送尼古丁（0.8mg/kg/天，含25或50μCi的[2'-(14)C]尼古丁，持续1至21天）。采集全脑和躯干血液。通过高压液相放射性色谱法测定[2'-(14)C]尼古丁及其代谢产物的浓度。注射10次后，脑中尼古丁、可替宁和去甲烟碱的浓度分别增加了2倍、12倍和9倍，在第5次注射后达到平台期。脑血比表明，随着注射次数增加，去甲烟碱在脑中的优先分布增强。在持续输注的21天期间，血液中尼古丁和去甲烟碱的浓度保持相对恒定，而脑中的浓度增加了约4倍。一般来说，在输注期间，脑和血液中的可替宁浓度没有变化。脑/血比表明，在尼古丁输注期间，尼古丁在脑中的分布增加。结果表明，重复给予尼古丁后，尼古丁及其代谢产物都会在脑中蓄积，并且表明不能从血浆可替宁或尼古丁浓度推断脑尼古丁浓度。因此，重复给予尼古丁后去甲烟碱的蓄积表明该代谢产物在尼古丁的神经药理学作用中起作用。
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