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ETHNOPHARMACOLOGICAL RELEVANCE The two Tinospora species, T. crispa and T. sinensis, native to Southeast Asia, are integral components of various traditional preparations with structure-functional claims to treat various disorders, including diabetes and inflammation. AIM OF THE STUDY To assure the safety of the botanical finished products, herb-drug interaction potential of T. crispa and T. sinensis were investigated by testing their extracts and compounds for potential in vitro activation of the pregnane X-receptor (PXR) and the modulation of CYP3A4 isozyme, selectively. MATERIALS AND METHODS A total of sixteen fully characterized phytochemicals from T. crispa and T. sinensis were initially evaluated for PXR activation by luciferase reporter gene assay. CYP3A4 inhibition studies were carried out for eleven compounds. In addition, docking studies were performed to elucidate the possible binding modes to the PXR by the compounds using computational methods. RESULTS Significant activation of PXR (2-fold) was observed for both extracts and non-polar fractions of T. crispa. Columbin showed significant activation of PXR (3-fold), which was comparable with the positive control, rifampicin. Vital interactions were predicted with docking simulation of PXR-columbin complex with critical amino acid residues (Trp-299) that are known for the activation of PXR. The methanolic extracts of T. crispa and T. sinensis also showed considerable CYP3A4 inhibition. CONCLUSION T. crispa and T. sinensis, both demonstrated the potential to mediate herb-drug interaction through PXR activation and inhibition of CYP3A4 isozyme. Moreover, the elucidation of the potential to induce herb-drug interaction, by the phytochemicals of these Tinospora plants, thereby supports the need for further investigation to establish the clinical relevancy of these constituents for possible adverse interactions with pharmaceutical drugs.