BOTANICAL/DRUG INTERACTIONS IN HIV: GLUCURONIDATION

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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.