The objective of this proposal is to profile the impact of pregnane X receptor (PXR)-mediated herb-drug interactions on the metabolism, pharmacokinetics, and toxicity of anti-HIV drugs. Herb- drug interactions are of great concern to clinicians and pharmacists in the HIV/AIDS community since anti-HIV drugs are frequently co-administered with herbal supplements. PXR is a ligand- dependent transcription factor, and activation of PXR upregulates the expression of genes encoding drug metabolizing enzymes and transporters. We recently examined 34 herbs that are frequently used in the HIV/AIDS community, and found 9 of them to be PXR-activating herbs. The current work will elucidate the active compounds from the complex mixtures of herbs that activate PXR. Our recent work also determined ritonavir (RTV), an anti-HIV drug, to be a victim of PXR-mediated drug-drug interactions. We will use RTV as an example to define the magnitude and mechanism(s) of herb-mediated PXR activation on the metabolism, pharmacokinetics, and toxicity of anti-HIV drugs. We will utilize genetically engineered cellular and mouse models of PXR in the proposed experiments. The findings from this work can be used to predict and prevent herb-drug interactions associated with anti-HIV drugs and many other drugs that are victims of PXR-mediated drug-drug interactions.
(Public health relevance statement) This project will elucidate activators of the pregnane X receptor (PXR) from herbs that are frequently used in the HIV/AIDS community. This project will also define the magnitude and mechanism(s) of herb-mediated PXR activation on the metabolism, pharmacokinetics, and toxicity of anti-HIV drugs. The results from this project are expected to provide the information necessary for designing PXR-based practice guidelines on the frequently used herbs in HIV/AIDS patients.
