Profiling Interactions Between Bicyclol and SLC/ABC Transporters: Advancing Clinical Safety and Efficacy in Combination Therapy

Objective Bicyclol, a hepatoprotective agent, is often used in combination with other drugs for liver diseases, including drug-induced liver injury (DILI), raising concerns about potential drug-drug interactions (DDIs). This study investigates the interaction between bicyclol and key transporters (OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, MATE2-K, P-gp, BCRP, BSEP) to predict transporter-related DDI risks. Methods Transporter interaction studies were conducted using cell lines or membrane vesicles overexpressing human uptake and efflux transporters. The substrate and inhibitory potential of bicyclol were systematically evaluated through transport and inhibition assays. The static model and criteria were applied to assess the risk of transporter-related DDIs in vivo . Results Bicyclol was not a substrate of above-mentioned transporters. Regarding inhibition, it was not an inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, MATE1, MATE2-K, or BSEP (IC 50 s > 100 μM). However, it was a marginal inhibitor of OCT2 (IC 50  = 76.2 μM), a weak inhibitor of P-gp (IC 50  = 123 μM), and a strong inhibitor of BCRP (IC 50  = 8.5 μM). The static model predicted that only BCRP would be inhibited in vivo by bicyclol, suggesting dose optimization might be required for BCRP substrates. Conclusions Here, we systematically elucidated the substrate and inhibition potential of bicyclol on major human drug transporters for the first time, which may provide the basis for rational co-administration of bicyclol, potentially broadening its clinical application.