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Nicotine Pharmacokinetics in Rat Brain and Blood by Simultaneous Microdialysis, Stable-Isotope Labeling, and UHPLC-HRMS: Determination of Nicotine Metabolites.
Analytical Chemistry ( IF 6.7 ) Pub Date : 2019-01-18 00:00:00 , DOI: 10.1021/acs.analchem.8b05078 Yan Xu 1 , Qidong Zhang 2 , Peng Li 2 , Guangfeng Hong 2 , Dingzhong Wang 2 , Junhui Liu 2 , Hao Zhou 3 , Guobi Chai 2 , Binbin Lu 2 , Shengbao He 4 , Wenjuan Zhang 2 , Shihao Sun 2 , Jianxun Zhang 2 , Jian Mao 2
Analytical Chemistry ( IF 6.7 ) Pub Date : 2019-01-18 00:00:00 , DOI: 10.1021/acs.analchem.8b05078 Yan Xu 1 , Qidong Zhang 2 , Peng Li 2 , Guangfeng Hong 2 , Dingzhong Wang 2 , Junhui Liu 2 , Hao Zhou 3 , Guobi Chai 2 , Binbin Lu 2 , Shengbao He 4 , Wenjuan Zhang 2 , Shihao Sun 2 , Jianxun Zhang 2 , Jian Mao 2
Affiliation
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The disposition and metabolism of nicotine in the brain is an important determinant of its exposure. We have developed a novel method for the dynamic determination of nicotine and its metabolites in rat brain and blood by simultaneous microdialysis sampling, stable-isotope labeling, and ultra high-performance liquid chromatography–high-resolution mass spectrometry (UHPLC–HRMS) assaying. Microdialysis probes were inserted into both the right striatum and jugular vein of Sprague–Dawley rats. The collections of dialystes after nicotine intraperitoneal injection were analyzed by the optimized UHPLC–HRMS. Nicotine-pyridyl-d4 was used as a metabolic tracer, and several stably labeled isotopes were applied to calibrate the in vivo recoveries of retrodialysis. The quadrupole-Orbitrap HRMS provided reliable characterization of the nicotine derivatives with less than 3.5 ppm mass measurement accuracy. Good precision and accuracy were obtained for different analytes within the predefined limits of acceptability and the range of the standard curve. Nicotine and its 11 metabolites were identified in most microdialysis samples from the blood and brain tissue samples. Besides cotinine as the main metabolic product of nicotine, trans-3′-hydroxy-cotinine, nicotine-N-oxide, and norcotinine were proven to be the second most abundant metabolites. The other seven nicotine products, including 4-oxo-4-(3-pyridyl)-butanoic acid, 4-hydroxy-4-(3-pyridyl)-butanoic acid, cotinine-N-oxide, nicotine-N-glucuronide, cotinine-N-glucuronide, and trans-3′- hydroxy-cotinine-O-glucuronide, which have not been determined previously in animal brain, were present in minor amounts. The pharmacokinetic profile of nicotine metabolites indicated that the metabolic characteristic of nicotine in the brain was relatively different from that in the blood. The present work would provide comprehensive evidence for clarifying the differences between nicotine metabolism in the brain and peripheral system.
中文翻译：
同时微透析，稳定同位素标记和UHPLC-HRMS在大鼠脑和血液中尼古丁的药代动力学：尼古丁代谢物的测定。
尼古丁在大脑中的分布和代谢是其暴露的重要决定因素。我们已经开发了一种通过同时进行微透析采样，稳定同位素标记和超高效液相色谱-高分辨率质谱（UHPLC-HRMS）测定来动态测定大鼠脑和血液中尼古丁及其代谢物的新方法。将微透析探针插入Sprague-Dawley大鼠的右纹状体和颈静脉。通过优化的UHPLC-HRMS分析尼古丁腹膜内注射后的透析液收集物。尼古丁-吡啶基-d 4代谢物示踪剂被用作代谢示踪剂，几种稳定标记的同位素被用于校准逆透析的体内回收率。四极杆Orbitrap HRMS提供了尼古丁衍生物的可靠表征，质量测量精度低于3.5 ppm。在可接受的预定范围和标准曲线范围内，对不同的分析物都获得了良好的精度和准确性。在大多数血液和脑组织样本的微透析样本中都鉴定出了尼古丁及其11种代谢物。除了可替宁是尼古丁的主要代谢产物外，反式-3'-羟基-烟碱，尼古丁-N氧化物和去甲烟碱被证明是第二丰富的代谢产物。其他七个尼古丁产品，包括4-氧代-4-（3-吡啶基）-丁酸，4-羟基-4-（3-吡啶基）-丁酸，可替宁-N-氧化物，尼古丁-N-葡糖醛酸，可替宁- ñ葡萄糖醛酸苷，和反式-3'-羟基cotinine- ö以前在动物脑中尚未测定的β-葡萄糖醛酸含量很小。尼古丁代谢物的药代动力学特征表明，尼古丁在大脑中的代谢特征与血液中的代谢特征相对不同。目前的工作将提供全面的证据，以澄清大脑和周围系统中尼古丁代谢之间的差异。
更新日期：2019-01-18
中文翻译：
同时微透析，稳定同位素标记和UHPLC-HRMS在大鼠脑和血液中尼古丁的药代动力学：尼古丁代谢物的测定。
尼古丁在大脑中的分布和代谢是其暴露的重要决定因素。我们已经开发了一种通过同时进行微透析采样，稳定同位素标记和超高效液相色谱-高分辨率质谱（UHPLC-HRMS）测定来动态测定大鼠脑和血液中尼古丁及其代谢物的新方法。将微透析探针插入Sprague-Dawley大鼠的右纹状体和颈静脉。通过优化的UHPLC-HRMS分析尼古丁腹膜内注射后的透析液收集物。尼古丁-吡啶基-d 4代谢物示踪剂被用作代谢示踪剂，几种稳定标记的同位素被用于校准逆透析的体内回收率。四极杆Orbitrap HRMS提供了尼古丁衍生物的可靠表征，质量测量精度低于3.5 ppm。在可接受的预定范围和标准曲线范围内，对不同的分析物都获得了良好的精度和准确性。在大多数血液和脑组织样本的微透析样本中都鉴定出了尼古丁及其11种代谢物。除了可替宁是尼古丁的主要代谢产物外，反式-3'-羟基-烟碱，尼古丁-N氧化物和去甲烟碱被证明是第二丰富的代谢产物。其他七个尼古丁产品，包括4-氧代-4-（3-吡啶基）-丁酸，4-羟基-4-（3-吡啶基）-丁酸，可替宁-N-氧化物，尼古丁-N-葡糖醛酸，可替宁- ñ葡萄糖醛酸苷，和反式-3'-羟基cotinine- ö以前在动物脑中尚未测定的β-葡萄糖醛酸含量很小。尼古丁代谢物的药代动力学特征表明，尼古丁在大脑中的代谢特征与血液中的代谢特征相对不同。目前的工作将提供全面的证据，以澄清大脑和周围系统中尼古丁代谢之间的差异。
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