豆腐果苷及其代谢产物时辰药动学研究

目的：研究不同时辰给药对豆腐果苷及其代谢产物药代动力学行为的影响。方法：建立并验证豆腐果苷及其3种Ⅰ相代谢产物高效液相色谱-质谱联用同时检测方法。分别在8∶00，14∶00及0∶00灌胃给予大鼠豆腐果苷50 mg/kg，眼底静脉丛采集血样，测得其血药浓度，对比在不同时间给药后原药及代谢产物的药物代谢动力学行为。结果：所建立的高效液相色谱串联质谱检测方法成功应用于灌胃给药后的大鼠血浆豆腐果苷及其3种代谢产物的同时检测。以AUC(0-t)做为吸收程度评价指标，原药、氧化产物、还原产物均为8∶00给药组>0∶00给药组>14∶00给药组；同一时间点原药与代谢产物比较，8∶00给药组、14∶00给药组、0∶00给药组均为：原药>还原产物>氧化产物。Cmax原药0∶00给药组>8∶00给药组>14∶00给药组，还原产物与氧化产物为8∶00给药组>14∶00给药组>0∶00给药组；Tmax原药与还原产物8∶00给药组>14∶00给药组>0∶00给药组，氧化产物8∶00给药组>0∶00给药组>14∶00给药组；以CLz/F为表征的清除情况，原药、还原产物与氧化产物均为14∶00给药组>0∶00给药组>8∶00给药组。 结论：本研究所选择的三个特定时间点，大鼠体内豆腐果苷原药及代谢产物在吸收与代谢过程显示出明显差异。8∶00给药吸收程度要大于其他两个时间点（P<0.01），14∶00给药原药及代谢产物体内清除快于其他时间点（P<0.01）。

Chronopharmacokinetics research of helicid and its metabolites

AIM: To study chronopharmacokinetics of helicid and its metabolites. METHODS: An HPLC-MS method for simultaneous determination of helicid and its three phase I metabolites were established and validated. At 8∶00, 14∶00 and 0∶00, the rats were given helicid 50 mg/kg by gavage, respectively. Blood samples were collected from ophthalmic venous plexus. Then plasma concentration was measured. Pharmacokinetic behaviors of the original drug and its metabolites after administration at different time points were calculated and compared. RESULTS: This established HPLC-MS/MS method was successfully applied to simultaneous determination of helicid and its three metabolites in rat plasma after intragastric administration. Using AUC(0-t) as evaluation index of degree of absorption, the original drug, oxidation product, and reduction product in the 8∶00 administration group were all >0∶00 administration group and >14∶00 administration group; at the same time point compared with the metabolites, 8∶00 administration group, 14∶00 administration group, and 0∶00 administration group were: original drug>reduced metabolite>oxidized metabolite. Cmax original drug 0∶00 administration group>8∶00 administration group>14∶00 administration group, reduction and oxidation metabolites were 8∶00 administration group>14∶00 administration group>0∶00 administration group. Tmax original drug and reduced metabolite 8∶00 administration group>14∶00 administration group>0∶00 administration group, oxidation metabolite 8∶00 administration group>0∶00 administration group>14∶00 administration group. Clearance characterized by CLz/F, the original drug, reduction metabolite and oxidation metabolite were all 14∶00 administration group>0∶00 administration group>8∶00 administration group. CONCLUSION: The three specific time points selected in this study, absorption and metabolism process of helicid and its metabolites showed great differences. The absorption degree of administration at 8∶00 was greater than the other two time points (P<0.01), and the elimination of the original drug and metabolites from the body at 14∶00 was much faster than that at other time points (P<0.01).