Residence times and half-lives of nicotine metabolites in rat brain after acute peripheral administration of [2'-(14)C]nicotine.
Residence times and half-lives of nicotine metabolites in rat brain after acute peripheral administration of [2'-(14)C]nicotine.
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发表时间：
1999-12
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通讯作者：
Omar A. Ghosheh;L. Dwoskin;Wen-kui Li;P. Crooks
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作者：
Omar A. Ghosheh;L. Dwoskin;Wen-kui Li;P. Crooks
测定大鼠急性外周尼古丁给药后尼古丁及其代谢物在脑内的滞留时间。我们假设尼古丁代谢物将在大脑中达到显著的药理浓度。用双标记放射化学和气相色谱-质谱法对S、S(-)-尼古丁在大鼠脑内的生物转化产物可替宁、去甲烟碱和去甲烟宁进行了结构鉴定。在大脑中还检测到两种未知的次要代谢物。测定尼古丁代谢物在脑内的半衰期。注射[2‘-(14)C]-(+/-)尼古丁(0.8 mg/kg)，并用高压-液体放射层析法分析放射性标记代谢物。尼古丁、可替宁和去甲烟碱的脑内半衰期分别为52、333和166分钟。尼古丁代谢物在大脑中的峰值浓度分别为300、70和7 nM。即使长期服用尼古丁后，可替宁在大脑中可能积累，但由于激活尼古丁受体诱导多巴胺释放，大脑中可替宁的浓度可能不足以产生神经药理效应。相反，急性尼古丁后大脑中去甲尼古丁的浓度接近发现的神经药理活性范围。根据这种代谢物的大脑半衰期，长期服用尼古丁很可能会在大脑中积聚去甲尼古丁。重要的是，去甲尼古丁也是烟草的主要生物碱成分。因此，作为烟草使用的结果，生物碱和新陈代谢形成的降尼古丁在大脑中的浓度可能达到足以产生药理作用的浓度。
The residence times of nicotine and its metabolites in rat brain after acute peripheral nicotine administration were determined. We hypothesize that nicotine metabolites will reach pharmacologically significant concentrations in brain. Cotinine, nornicotine, and norcotinine were structurally identified by dual label radiochemical and gas chromatography-mass spectrometric analysis as biotransformation products of nicotine present in rat brain after s. c. injection of S(-)-nicotine. Two unidentified minor metabolites were also detected in brain. The half-lives in brain of nicotine metabolites were determined after a single s.c. injection of [2'-(14)C]-(+/-)nicotine (0.8 mg/kg) and analysis of radiolabeled metabolites by high pressure-liquid radiochromatography. The brain half-lives of nicotine, cotinine, and nornicotine were 52, 333, and 166 min, respectively. Peak brain concentrations of nicotine metabolites were 300, 70, and 7 nM for cotinine, nornicotine, and norcotinine, respectively. Even with potential accumulation of cotinine in brain after chronic nicotine administration, it is likely that the brain concentration of cotinine will be insufficient to produce neuropharmacological effects resulting from activation of nicotinic receptors to induce dopamine release. Conversely, the concentration of nornicotine in brain after acute nicotine approaches the range found to be neuropharmacologically active. It is likely that nornicotine will accumulate in brain on chronic nicotine administration based on the brain half-life of this metabolite. Importantly, nornicotine is also a major alkaloidal component of tobacco. Thus, as a consequence of tobacco use, alkaloidal and metabolically formed nornicotine may reach concentrations in brain sufficient to produce pharmacological effects.