Genetic polymorphisms of OATP1B1 influence the inhibitory potency of inhibitors and their pre-incubation effect

Organic anion transporting polypeptide (OATP) 1B1 mediates hepatic drug uptake, and its inhibition can trigger clinically significant drug-drug interactions (DDIs). However, the impact of OATP1B1 genetic variants, such as *1b, *5, and *15, on OATP1B1 inhibition remains unclear. This study compared the inhibitory potencies ( K i ) of sulfobromophthalein (BSP), cobicistat (COB), cyclosporine (CsA), glecaprevir (GLE), lopinavir (LOP), rifampicin (RFP), and tacrolimus (TAC) on OATP1B1 variants using 2’,7’-dichlorofluorescein and pitavastatin (PTV) as substrates. Pre-incubation-dependent K i shifts were also evaluated for PTV. Without pre-incubation, BSP and TAC exhibited significantly reduced inhibitory potency (increased K i ) against OATP1B1*5 and *15 compared to *1a, with a marked increase in K i (> tenfold) observed for TAC. Conversely, inhibitory potency of CsA, GLE, and LOP exhibited minimal variation (< twofold) across variants. Upon pre-incubation, a shift in K i values (to 0.066–0.13 fold) was observed for CsA across all variants and for LOP, RFP, and TAC in OATP1B1*5 and 15, while no impact in COB and GLE. These findings suggest that OATP1B1 polymorphisms may influence inhibitor potency and DDI magnitude, indicating that genotype could be an important factor in certain cases.