BOTANICAL/DRUG INTERACTIONS IN HIV: GLUCURONIDATION

描述(由申请人提供)：补充和替代药物(CAM)被广泛使用，目的是改善一般健康，补充传统药物或作为某些疾病的主要治疗方法。艾滋病毒/艾滋病患者使用替代药物的比例高于正常人群。然而，尽管CAMS与常规抗HIV药物之间的相互作用潜力很大，但这些潜在的相互作用还没有得到广泛的研究。这种相互作用可能会被忽视，因为抗艾滋病毒药物的不良反应普遍发生，一些抗艾滋病毒药物在药物处置方面存在广泛的对象间差异--即使在良好的对照研究中--以及很少有医生得到艾滋病毒/艾滋病患者关于使用CAM的通知。有必要更好地了解潜在的CAM-药物相互作用，以减少可能的不良反应或提高所用药物的疗效。这种相互作用也可能是有益的，如果它们提供了减少药物使用或改善传统药物的一些不良影响的机制。在这里，我们建议研究被声称或报道为葡萄糖醛酸化的调节剂的CAM之间的潜在相互作用，葡萄糖醛酸化是一种常见的接合代谢途径，对于消除叠氮胸苷、阿巴卡韦、依沙韦林和霉酚酸很重要。葡萄糖醛酸化是第二相代谢的主要途径，但对氧化代谢的研究较少。药物的葡萄糖醛酸化作用降低活性(通常)并促进代谢物在尿液和胆汁中的排泄。在胆汁中排泄的葡萄糖醛酸苷通常被肠道-肝脏循环，在那里它们被肠道中的β-葡萄糖醛酸酶切割。将研究三种葡萄糖醛酸化调节剂，胡椒碱、西利姆林和葡萄糖酸酯，以研究它们与抗HIV药物的潜在相互作用。葡萄糖酸的内酯形式是一种众所周知的、广泛使用的β-葡萄糖醛酸酶抑制剂。胡椒碱和水飞蓟宾是葡萄糖醛酸化反应的有效和广泛的抑制剂，也可以抑制氧化酶系统。这三种可能对葡萄糖醛酸化有抑制和诱导作用的CAM，将在体外和体内进行检测，包括在健康志愿者身上进行单剂临床研究，以确定它们是否相互作用或调节抗艾滋病毒药物的处置。此外，还将在体外检测胡椒碱是否有可能抑制抗HIV药物的氧化代谢，如蛋白酶抑制剂。

DESCRIPTION (provided by applicant): Complementary and alternative medicines (CAM) are widely used with the goal of improving general health, to supplement conventional medicine or as primary therapy for some ailments. The use of alternative medicines by HIV/AIDS patients is higher than the normal population. However, though the potential for interactions between CAMs and conventional anti-HIV drugs is large, these potential interactions have not been extensively investigated. Such interactions may go unnoticed due to the common incidence of adverse effects with anti-HIV drugs, the wide inter-subject variability in drug disposition of some anti-HIV drugs - even in well controlled studies - and the fact that few physicians are notified by their patients with HIV/AIDS about the use of CAM. There is need to better understand potential CAM-drug interactions in order to reduce possible adverse effects or enhance efficacy of the drugs being employed. Such interactions may also be beneficial, if they provided mechanisms to reduce drug utilization or ameliorate some adverse effects of conventional drugs. Here we propose to investigate potential interactions between CAM that are claimed or reported to be modulators of glucuronidation, a common conjugative metabolic pathway important for the elimination of azidothymidine, abacavir, efavirenz,and mycophenolic acid. Glucuronidation is the major Phase II metabolic pathway, but is much less studied that oxidative metabolism. Glucuronidation of drugs reduces activity (usually) and promotes the excretion of the metabolite in urine and bile. Glucuronides excreted in bile are often subject to enterohepatic recycling where they are cleaved by intestinal betaglucuronidase. Three modulators of glucuronidation, piperine, sylimarin and glucarate, will be studied for their potential interactions with anti-HIV drugs. The internal lactone form of glucarate is a well-known, widely used inhibitor of beta-glucuronidase. Piperine and silybin are potent and broad inhibitor of glucuronidation and can also inhibit oxidative enzyme systems. These three CAMs, with possible inhibitory and inductive effects on glucuronidation, will be examined in vitro and in vivo, including single dose clinical studies in healthy volunteers, to determine if they interact or modulate the disposition of anti-HIV drugs. Piperine will also be examined in vitro for potential inhibition of oxidative metabolism of anti-HIV drugs such as the protease inhibitors.