BOTANICAL/DRUG INTERACTIONS IN HIV: GLUCURONIDATION

描述（由申请人提供）：补充和替代药物（CAM）被广泛用于改善一般健康，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和常规抗HIV药物之间相互作用的可能性很大，但这些潜在的相互作用尚未得到广泛研究。由于抗HIV药物不良反应的常见发生率，某些抗HIV药物的药物处置存在广泛的受试者间差异（即使在对照良好的研究中），以及很少有医生被HIV/AIDS患者告知使用CAM，因此此类相互作用可能未被注意到。需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利用或改善常规药物的某些不良反应的机制。在这里，我们建议调查CAM之间的潜在相互作用，声称或报告是葡萄糖醛酸化，一种常见的共轭代谢途径的重要消除叠氮胸苷，阿巴卡韦，依法韦仑，麦考酚酸的调节剂。葡萄糖醛酸化是主要的II相代谢途径，但相对于氧化代谢研究较少。药物的葡萄糖醛酸化降低活性（通常）并促进代谢产物在尿液和胆汁中的排泄。胆汁中排泄的葡萄糖醛酸苷通常会经过肠肝再循环，在此被肠β-葡萄糖醛酸酶裂解。 将研究三种葡萄糖醛酸化调节剂胡椒碱、sylimarin和glucarate与抗HIV药物的潜在相互作用。葡萄糖二酸的内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。甘草碱和水飞蓟宾是葡萄糖醛酸化的有效和广泛的抑制剂，也可以抑制氧化酶系统。这三种CAM可能对葡萄糖醛酸化具有抑制和诱导作用，将在体外和体内进行检查，包括在健康志愿者中进行的单次给药临床研究，以确定它们是否与抗HIV药物相互作用或调节抗HIV药物的分布。还将在体外检查马槟榔碱对抗HIV药物（如蛋白酶抑制剂）氧化代谢的潜在抑制作用。

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.