Ramu K, Baker J K
Department of Medicinal Chemistry, University of Mississippi, University 38677, USA.
J Pharm Sci. 1997 Aug;86(8):915-20. doi: 10.1021/js960424k.
A method was developed to quantitate the glucuronide conjugates (phase II metabolites, log P = 0.6-1.8) of the phase I hydroxylated metabolites (log P = 2.6-2.7) of beta-arteether (2) (log P = approximately 4.0) in rat plasma and urine. The biological fluids were extracted with a C-18 solid-phase cartridge, then subjected to analysis by thermospray high-performance liquid chromatography/mass spectroscopy with a C-18 reversed-phase analytical column in the selected ion monitoring mode. The detection limits for these glucuronide conjugates in plasma and urine ranged from 25 to 60 ng/mL, and the detection limits were appropriate for the biological activity of these glucuronide conjugates in plasma. Following intravenous administration of arteether (11.6 mg/kg), the formation of these glucuronide conjugates in rat urine was undetected (below detection limit) over 24 h. However, in rat plasma, formation of 9alpha-hydroxyarteether glucuronide (13; 255 ng/mL, IC50 = 6560 ng/mL, log P = 0.93) was noted at 15 min post-injection. Although several of the glucuronide metabolites of arteether retained sufficient in vitro antimalarial activity to be potentially useful antimalarial agents if administered as prodrugs, the levels of the glucuronides formed from arteether were too low to contribute to the antimalarial activity observed for the parent compound.
已开发出一种方法，用于定量测定大鼠血浆和尿液中蒿甲醚（2）（log P约为4.0）的I相羟基化代谢物（log P = 2.6 - 2.7）的葡糖醛酸缀合物（II相代谢物，log P = 0.6 - 1.8）。生物样品用C-18固相柱提取，然后在选定离子监测模式下，使用C-18反相分析柱通过热喷雾高效液相色谱/质谱进行分析。这些葡糖醛酸缀合物在血浆和尿液中的检测限为25至60 ng/mL，该检测限适用于这些葡糖醛酸缀合物在血浆中的生物活性。静脉注射蒿甲醚（11.6 mg/kg）后，在24小时内未检测到大鼠尿液中这些葡糖醛酸缀合物的形成（低于检测限）。然而，在大鼠血浆中，注射后15分钟时可检测到9α-羟基蒿甲醚葡糖醛酸（13；255 ng/mL，IC50 = 6560 ng/mL，log P = 0.93）的形成。尽管蒿甲醚的几种葡糖醛酸代谢物保留了足够的体外抗疟活性，若作为前药给药可能是有用的抗疟剂，但蒿甲醚形成的葡糖醛酸水平过低，无法对母体化合物观察到的抗疟活性产生贡献。
