Tevell Annica, Lennernäs Hans, Jönsson Mats, Norlin Maria, Lennernäs Bo, Bondesson Ulf, Hedeland Mikael
Department of Medicinal Chemistry, Division of Analytical Pharmaceutical Chemistry, Uppsala University, Uppsala, Sweden.
Drug Metab Dispos. 2006 Jun;34(6):984-92. doi: 10.1124/dmd.105.008516. Epub 2006 Mar 15.
A new metabolic scheme of flutamide is proposed in this article. Some patients treated with flutamide, a nonsteroidal antiandrogen, have developed severe hepatic dysfunction. Toxic metabolites have been proposed to be responsible for these negative effects. In this study, the qualitative aspects of the in vitro metabolism of flutamide in liver microsomes from human, dog, pig, and rat were evaluated. A direct comparison of the flutamide metabolism in liver and prostate microsomes from pig was made, and the in vivo metabolism of flutamide was investigated in urine from orally treated prostate cancer patients. Liquid chromatography/tandem mass spectrometry was used for analysis. The mass spectrometer was equipped with an electrospray interface and operated in the negative ion mode. In liver microsomes from pig, dog, and rat, extensive hydroxylation of flutamide occurred. One, two, or three hydroxy groups were attached, and isomeric forms were detected for both monohydroxylated and trihydroxylated drug. In pig liver microsomes, isomers of a third metabolite, hydroxylated 4-nitro-3-(trifluoromethyl)-aniline, were also found after incubation with either flutamide or 2-hydroxyflutamide. In human liver microsomes, the pharmacologically active 2-hydroxyflutamide was the only metabolite detected. Several phase I metabolites as well as four intact phase II metabolites could be recovered from the urine samples. For the first time in humans, glucuronic acid conjugates of hydroxylated 4-nitro-3-(trifluoromethyl)-aniline, and mono- and dihydroxylated flutamide were identified, together with hydroxylated 4-nitro-3-(trifluoromethyl)-aniline conjugated with sulfate. In addition, one mercapturic acid conjugate of hydroxylated flutamide, probably formed from flutamide via a reactive intermediate, was detected.
本文提出了氟他胺的一种新代谢方案。一些接受非甾体抗雄激素药物氟他胺治疗的患者出现了严重的肝功能障碍。有毒代谢产物被认为是这些不良反应的原因。在本研究中，评估了氟他胺在人、狗、猪和大鼠肝脏微粒体中的体外代谢定性方面。对猪肝脏和前列腺微粒体中氟他胺的代谢进行了直接比较，并对口服治疗的前列腺癌患者尿液中的氟他胺体内代谢进行了研究。采用液相色谱/串联质谱法进行分析。质谱仪配备电喷雾接口，以负离子模式运行。在猪、狗和大鼠的肝脏微粒体中，氟他胺发生了广泛的羟基化。连接了一个、两个或三个羟基，并且检测到单羟基化和三羟基化药物的异构体形式。在猪肝微粒体中，与氟他胺或2-羟基氟他胺孵育后，还发现了第三种代谢产物羟基化4-硝基-3-(三氟甲基)-苯胺的异构体。在人肝脏微粒体中，检测到的唯一代谢产物是具有药理活性的2-羟基氟他胺。从尿液样本中可以回收几种I相代谢产物以及四种完整的II相代谢产物。在人类中首次鉴定出羟基化4-硝基-3-(三氟甲基)-苯胺的葡萄糖醛酸共轭物、单羟基化和二羟基化氟他胺，以及与硫酸盐共轭的羟基化4-硝基-3-(三氟甲基)-苯胺。此外，还检测到一种羟基化氟他胺的巯基尿酸共轭物，可能是由氟他胺通过活性中间体形成的。
