Yan Bei, Wang Guangji, Sun Jianguo, Li Xiaoyu, Zheng Yuanting, Ai Hua, Lv Hua, Wu Xiaoming, Xu Jinyi
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, No. 24, Tong Jia Xiang Street, Nanjing 210009, People's Republic of China.
Biomed Chromatogr. 2007 Sep;21(9):912-24. doi: 10.1002/bmc.822.
5-n-Butyl-4-{4-[2-(1H-tetrazole-5-yl)-1H-pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2-(2,6-dichloridephenyl)-3H-1,2,4-triazol-3-one (1b), a new non-peptide angiotensin type 1 receptor antagonist, has been observed to play a positive role in the treatment of hypertension in preclinical tests. Rats were dosed with the drug, and the major metabolites in the bile were separated by gradient elution high-performance liquid chromatography. HPLC-diode array detection-mass spectrometry, HPLC-electrospray ionization MS/MS methods in negative ion mode and collision-induced dissociation were used to elucidate the structures of the major metabolites of 1b. One dihydroxylated 1b (M1), two monohydoxylated 1b (M2, M3) and one 1b monoglucuronide (M5) were found in male rat bile; however, three monohydoxylated 1b (M2, M3, M4) and one 1b monoglucuronide (M5) were found in female rat bile. These metabolites greatly differ in amount between male and female rat bile.
5-正丁基-4-{4-[2-(1H-四氮唑-5-基)-1H-吡咯-1-基]苯甲基}-2,4-二氢-2-(2,6-二氯苯基)-3H-1,2,4-三唑-3-酮（1b）是一种新型非肽类血管紧张素1型受体拮抗剂，在临床前试验中已观察到其在高血压治疗中发挥积极作用。给大鼠服用该药物后，通过梯度洗脱高效液相色谱法分离胆汁中的主要代谢产物。采用HPLC-二极管阵列检测-质谱法、负离子模式下的HPLC-电喷雾电离MS/MS方法以及碰撞诱导解离来阐明1b主要代谢产物的结构。在雄性大鼠胆汁中发现了一种二羟基化的1b（M1）、两种单羟基化的1b（M2、M3）和一种1b单葡萄糖醛酸苷（M5）；然而，在雌性大鼠胆汁中发现了三种单羟基化的1b（M2、M3、M4）和一种1b单葡萄糖醛酸苷（M5）。这些代谢产物在雄性和雌性大鼠胆汁中的含量差异很大。
