目的 研究吸入和ig给药苯甲酸槟榔碱后槟榔碱及其代谢产物槟榔次碱和槟榔碱-N-氧化物在大鼠血浆和组织中的药动学特征及差异。方法 SD大鼠分为吸入组和ig组，药动学和组织分布研究的给药剂量分别为4.06、16.24 mg·kg^-1，给药后于不同时间点采集生物样品；采用超高效液相色谱串联三重四级杆质谱（UPLC-MS/MS）法测定槟榔碱、槟榔次碱和槟榔碱-N-氧化物的血药浓度，绘制血药浓度-时间曲线，计算主要药动学参数。结果 建立的UPLC-MS/MS方法符合生物样品测定的要求。与ig给药组相比，吸入苯甲酸槟榔碱后槟榔碱和槟榔碱-N-氧化物的达峰时间(t_max)和平均滞留时间（MRT）均显著延长（P<0.01），提示其吸收和消除速度更慢，而槟榔次碱的t_max显著缩短（P<0.01），吸收速度较快，但其半衰期(t_1/2)和MRT仍显著延长（P<0.01），表明消除速度较慢。组织分布方面，2种给药方式下3种成分在各组织中的暴露量存在差异：与ig给药相比，吸入苯甲酸槟榔碱后，大鼠肝脏中槟榔次碱和槟榔碱-N-氧化物的血药浓度-时间曲线下面积(AUC_0～t)和峰浓度(C_max)均显著降低（P<0.01）；肺组织中槟榔碱、槟榔次碱的C_max、AUC_0～t显著增大（P<0.01）；脑组织中槟榔次碱和槟榔碱-N-氧化物的C_max、AUC_0～t显著升高（P<0.05、0.01），而槟榔碱的C_max显著降低（P<0.01）；肾组织中槟榔碱和槟榔碱-N-氧化物的C_max、AUC_0～t均显著升高（P<0.01），槟榔次碱AUC_0～t显著降低（P<0.01）；睾丸组织中未检测到槟榔碱、槟榔次碱，且槟榔碱-N-氧化物的C_max显著降低（P<0.01）。结论 苯甲酸槟榔碱经吸入给药后，可增加槟榔碱及其代谢产物在大鼠肺组织中的分布，同时降低肝和睾丸组织中的分布，从而在一定程度上减轻大鼠肝脏负担，为槟榔碱的后续深入研究及临床安全用药提供参考。

Objective To investigate the pharmacokinetic characteristics and differences of arecoline, arecoline-N-oxide and arecolidine in plasma and tissues of rats after inhalation and intragastric administration of arecoline benzoate. Methods SD rats were divided into inhalation group and intragastric administration group. The doses for pharmacokinetic and tissue distribution studies were 4.06 and 16.24 mg·kg^-1, respectively. Biological samples were collected at different time points after administration. The blood concentrations of arecoline, arecolidine and arecoline-N-oxide were determined by ultra-performance liquid chromatography-tandem triple quadrupole mass spectrometry（UPLC-MS/MS）. The blood concentration-time curves were plotted and the main pharmacokinetic parameters were calculated. Results The established UPLC-MS/MS method met the requirements for the determination of biological samples. Compared with the intragastric administration group, the peak time(t_max) and mean residence time（MRT） of arecoline and arecoline-N-oxide after inhalation of arecoline benzoate were significantly prolonged（P＜0.01）, suggesting that their absorption and elimination rates were slower. However, the t_max of arecolidine was significantly shortened（P＜0.01）, indicating a faster absorption rate. However, its half-life(t_1/2) and MRT were still significantly prolonged（P＜0.01）, suggesting a slower elimination rate. In terms of tissue distribution, there were differences in the exposure of the three components in various tissues between the two administration methods. Compared with intragastric administration, after inhalation of arecoline benzoate, the area under the blood concentrationtime curve(AUC_0～t) and peak concentration(C_max) of arecolidine and arecoline-N-oxide in the liver of rats were significantly decreased（P＜0.01）; the C_max and AUC_{0～t of arecoline and arecolidine in the lung tissue were significantly increased（P＜0.01）; the Cmax and AUC0～t of arecolidine and arecoline-N-oxide in the brain tissue were significantly increased（P＜0.05, 0.01）, while the Cmax of arecoline was significantly decreased（P＜0.01）; the Cmax and AUC0～t of arecoline and arecoline-N-oxide in the kidney tissue were significantly increased（P＜0.01）, while the AUC0～t of arecolidine was significantly decreased（P＜0.01）; arecoline and arecolidine were not detected in the testis tissue, and the Cmax of arecoline-N-oxide was significantly decreased（P＜0.01）. Conclusion Inhalation administration of arecoline benzoate can increase the distribution of arecoline and its metabolites in the lung tissue of rats, while reducing their distribution in the liver and testis tissues, thereby reducing the burden on the liver to a certain extent, providing a reference for the subsequent in-depth research and clinical safe use of arecoline.}

R969.1

中国中医科学院优秀青年科技人才培养专项(ZZ13-YQ-058、ZZ17-YQ-020);中国中医科学院科技创新工程重大攻关项目(CI2021A04615); 广东省基础与应用基础研究基金资助项目(2023A1515011743)