Jäger W, Zembsch B, Wolschann P, Pittenauer E, Senderowicz A M, Sausville E A, Sedlacek H H, Graf J, Thalhammer T
Institute of Pharmaceutical Chemistry, University of Vienna, Austria.
Life Sci. 1998;62(20):1861-73. doi: 10.1016/s0024-3205(98)00152-0.
Flavopiridol (FLAP) is a promising novel chemotherapeutic agent currently undergoing clinical phase I trials. To examine hepatic metabolism and biliary disposition of FLAP we applied the isolated perfused rat liver system. Besides FLAP two metabolites were detected by high performance liquid chromatography in bile and perfusate. Twenty-five min after FLAP (30 microM) addition to the perfusion medium, biliary secretion of metabolite 1 and 2 reached a maximum of 1.04 +/- 0.52 and 11.34 +/- 4.72 nmol/g.liver.min, respectively. Biliary excretion of parent FLAP, however, continuously increased for 60 min up to 406 +/- 134 pmol/g liver.min. In the perfusate, metabolite 1 was below detection limit and release of metabolite 2 was low (2.8 +/- 0.7 pmol/g liver.min after 60 min). Enzymatic hydrolysis with beta-glucuronidase, mass spectroscopy and electron absorption spectroscopy revealed that both metabolites are monoglucuronides with the glucuronide in position 5 and 7 of the flavonoid core, respectively. The amount of FLAP, metabolite 1 and metabolite 2 excreted into bile during the 60 min of perfusion was 1.94 +/- 0.91, 5.15 +/- 1.95 and 57.29 +/- 23.60% of FLAP cleared from the perfusate during 60 min, respectively. In contrast to the structurally similar flavonoids genistein and daidzein, no inhibition of UDP-glucuronyltransferase with methylumbelliferone as a substrate was observed indicating that different UDP-glucuronyltransferase isoforms are involved in FLAP metabolism. In conclusion, we find that glucuronidation is the major mechanism of hepatic FLAP biotransformation. Metabolites are mainly excreted into bile but also released into systemic circulation. The pharmacological and toxicological effects of these metabolites remain to be elucidated.
黄酮哌啶醇（FLAP）是一种很有前景的新型化疗药物，目前正处于临床I期试验阶段。为了研究FLAP的肝脏代谢和胆汁排泄情况，我们应用了离体灌注大鼠肝脏系统。除了FLAP，通过高效液相色谱法在胆汁和灌注液中检测到了两种代谢产物。在向灌注介质中添加FLAP（30微摩尔）后25分钟，代谢产物1和2的胆汁分泌量分别达到最大值，即1.04±0.52和11.34±4.72纳摩尔/克肝脏·分钟。然而，母体FLAP的胆汁排泄在60分钟内持续增加，直至达到406±134皮摩尔/克肝脏·分钟。在灌注液中，代谢产物1低于检测限，代谢产物2的释放量较低（60分钟后为2.8±0.7皮摩尔/克肝脏·分钟）。用β-葡萄糖醛酸酶进行酶解、质谱分析和电子吸收光谱分析表明，这两种代谢产物均为单葡萄糖醛酸苷，葡萄糖醛酸分别位于黄酮类核心结构的5位和7位。在60分钟的灌注过程中，排泄到胆汁中的FLAP、代谢产物1和代谢产物2的量分别占60分钟内从灌注液中清除的FLAP的1.94±0.91%、5.15±1.95%和57.29±23.60%。与结构相似的黄酮类化合物染料木黄酮和大豆苷元不同，未观察到以甲基伞形酮为底物时UDP-葡萄糖醛酸基转移酶受到抑制，这表明不同的UDP-葡萄糖醛酸基转移酶同工型参与了FLAP的代谢。总之，我们发现葡萄糖醛酸化是肝脏中FLAP生物转化的主要机制。代谢产物主要排泄到胆汁中，但也释放到体循环中。这些代谢产物的药理和毒理作用仍有待阐明。
