目的 研究吸入和ig給藥苯甲酸檳榔堿后檳榔堿及其代謝產(chǎn)物檳榔次堿和檳榔堿-N-氧化物在大鼠血漿和組織中的藥動(dòng)學(xué)特征及差異。方法 SD大鼠分為吸入組和ig組，藥動(dòng)學(xué)和組織分布研究的給藥劑量分別為4.06、16.24 mg·kg^-1，給藥后于不同時(shí)間點(diǎn)采集生物樣品；采用超高效液相色譜串聯(lián)三重四級(jí)桿質(zhì)譜（UPLC-MS/MS）法測(cè)定檳榔堿、檳榔次堿和檳榔堿-N-氧化物的血藥濃度，繪制血藥濃度-時(shí)間曲線，計(jì)算主要藥動(dòng)學(xué)參數(shù)。結(jié)果 建立的UPLC-MS/MS方法符合生物樣品測(cè)定的要求。與ig給藥組相比，吸入苯甲酸檳榔堿后檳榔堿和檳榔堿-N-氧化物的達(dá)峰時(shí)間(t_max)和平均滯留時(shí)間（MRT）均顯著延長(zhǎng)（P<0.01），提示其吸收和消除速度更慢，而檳榔次堿的t_max顯著縮短（P<0.01），吸收速度較快，但其半衰期(t_1/2)和MRT仍顯著延長(zhǎng)（P<0.01），表明消除速度較慢。組織分布方面，2種給藥方式下3種成分在各組織中的暴露量存在差異：與ig給藥相比，吸入苯甲酸檳榔堿后，大鼠肝臟中檳榔次堿和檳榔堿-N-氧化物的血藥濃度-時(shí)間曲線下面積(AUC_0～t)和峰濃度(C_max)均顯著降低（P<0.01）；肺組織中檳榔堿、檳榔次堿的C_max、AUC_0～t顯著增大（P<0.01）；腦組織中檳榔次堿和檳榔堿-N-氧化物的C_max、AUC_0～t顯著升高（P<0.05、0.01），而檳榔堿的C_max顯著降低（P<0.01）；腎組織中檳榔堿和檳榔堿-N-氧化物的C_max、AUC_0～t均顯著升高（P<0.01），檳榔次堿AUC_0～t顯著降低（P<0.01）；睪丸組織中未檢測(cè)到檳榔堿、檳榔次堿，且檳榔堿-N-氧化物的C_max顯著降低（P<0.01）。結(jié)論 苯甲酸檳榔堿經(jīng)吸入給藥后，可增加檳榔堿及其代謝產(chǎn)物在大鼠肺組織中的分布，同時(shí)降低肝和睪丸組織中的分布，從而在一定程度上減輕大鼠肝臟負(fù)擔(dān)，為檳榔堿的后續(xù)深入研究及臨床安全用藥提供參考。

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

中國(guó)中醫(yī)科學(xué)院優(yōu)秀青年科技人才培養(yǎng)專項(xiàng)(ZZ13-YQ-058、ZZ17-YQ-020);中國(guó)中醫(yī)科學(xué)院科技創(chuàng)新工程重大攻關(guān)項(xiàng)目(CI2021A04615); 廣東省基礎(chǔ)與應(yīng)用基礎(chǔ)研究基金資助項(xiàng)目(2023A1515011743)