Herb-Drug Glucuronidation Interactions

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DESCRIPTION (provided by applicant): Millions of Americans use herbal supplements to promote their health and wellness, many of them in combination with prescription medications. Accordingly, serious adverse herb- drug interactions resulting from the induction or inhibition of cytochrome P450 enzymes and/or the efflux transporter P-glycoprotein have been reported. However, there is a gap in our evidence-based knowledge regarding the potential of herbal supplements to interact with medications that undergo conjugative metabolism by uridine diphosphate glucuronosyl transferase (UGT) enzymes. Our laboratory has recently identified herbal supplements that strongly inhibit UGT-mediated metabolism. Based on these data, the objective of this application is to determine the extent to which commonly used herbal supplements can inhibit UGT enzymes in humans. The central hypothesis is that taking herbal supplements will alter the pharmacokinetics of a drug eliminated predominately by UGT-mediated metabolism. The goals of this project are to determine in healthy volunteers: 1) the effect of prolonged Ginkgo biloba administration on mycophenolic acid pharmacokinetics; and 2) the effect of green tea leaf extract administration on raloxifene pharmacokinetics. These drugs represent two of the top selling medications for which glucuronidation is the primary route of elimination; increased blood concentrations for each of these drugs can have dire consequences. It is important for human health to understand how herbal supplements influence the UGT-mediated metabolism of medications, as this will fill a significant gap in knowledge. This translational research will provide critical information on the extent to which selected herbal supplements alter the disposition of mycophenolic acid and raloxifene, two clinically important UGT substrates. PUBLIC HEALTH RELEVANCE: Herb-drug interactions continue to be a significant public health concern and the prevalence of herbal supplement use is substantial. The research proposed is significant because it is expected to provide evidence-based knowledge on the potential for herb-drug glucuronidation interactions, which will ultimately help health care providers anticipate potential herb-drug interactions and contribute to rational adjustments in therapy management.