Inhibition of ABC transporters by sorafenib and lenvatinib: implications for drug-induced cholestasis

Sorafenib and lenvatinib are systemic treatments for hepatocellular carcinoma. They often exhibit high intersubject pharmacokinetic variability and can cause drug-induced liver injury, yet the underlying mechanisms are poorly understood. Inhibition of some ATP-binding cassette (ABC) transporters, such as bile salt export pump (BSEP; <i>ABCB11</i>) and multidrug resistance-associated protein 2 (MRP2; <i>ABCC2</i>), which are involved in bile acid disposition, may lead to cholestatic liver injury.In this study, we investigated the inhibitory effects of sorafenib and lenvatinib on selected ABC transporters in membrane vesicles and sandwich-culture human hepatocytes (SCHH) using fluorescent probe substrates.The BSEP-mediated tauro-nor-THCA-24-DBD uptake was inhibited by sorafenib, with half-maximal inhibitory concentrations (IC₅₀) of 30.1 μM. Transport of Lucifer yellow by BCRP was strongly inhibited by sorafenib (IC₅₀ = 2.9 μM). Only sorafenib affected MRP2 activity (IC₅₀ = 15.6 µM). Both drugs showed comparable inhibition potency on P-gp with IC₅₀ values of 12.4 μM for sorafenib and 13.9 μM for lenvatinib. Unlike lenvatinib, sorafenib decreased the biliary excretion of tauro-nor-THCA-24-DBD, a probe substrate of BSEP, in SCHH by over 40%.In conclusion, sorafenib exhibited a more pronounced inhibition of ABC transporters, including BCRP, BSEP and MRP2, than lenvatinib, which could contribute to cholestatic liver injury. Sorafenib and lenvatinib are systemic treatments for hepatocellular carcinoma. They often exhibit high intersubject pharmacokinetic variability and can cause drug-induced liver injury, yet the underlying mechanisms are poorly understood. Inhibition of some ATP-binding cassette (ABC) transporters, such as bile salt export pump (BSEP; <i>ABCB11</i>) and multidrug resistance-associated protein 2 (MRP2; <i>ABCC2</i>), which are involved in bile acid disposition, may lead to cholestatic liver injury. In this study, we investigated the inhibitory effects of sorafenib and lenvatinib on selected ABC transporters in membrane vesicles and sandwich-culture human hepatocytes (SCHH) using fluorescent probe substrates. The BSEP-mediated tauro-nor-THCA-24-DBD uptake was inhibited by sorafenib, with half-maximal inhibitory concentrations (IC₅₀) of 30.1 μM. Transport of Lucifer yellow by BCRP was strongly inhibited by sorafenib (IC₅₀ = 2.9 μM). Only sorafenib affected MRP2 activity (IC₅₀ = 15.6 µM). Both drugs showed comparable inhibition potency on P-gp with IC₅₀ values of 12.4 μM for sorafenib and 13.9 μM for lenvatinib. Unlike lenvatinib, sorafenib decreased the biliary excretion of tauro-nor-THCA-24-DBD, a probe substrate of BSEP, in SCHH by over 40%. In conclusion, sorafenib exhibited a more pronounced inhibition of ABC transporters, including BCRP, BSEP and MRP2, than lenvatinib, which could contribute to cholestatic liver injury.