Inhibition of Four Anaplastic Lymphoma Kinase Inhibitors on the Activity of Human UDP-Glucuronosyltransferases and Prediction of Drug-Drug Interactions.

Anaplastic lymphoma kinase (ALK) inhibitors have shown remarkable efficacy in targeted therapy for non-small cell lung cancer (NSCLC). However, it is worth noting that they may cause clinical drug-drug interactions (DDIs) by inhibiting the activities of drug-metabolizing enzymes, thereby leading to unnecessary side effects. This study sought primarily to characterize the inhibition effects of four well-known ALK inhibitors, crizotinib, ceritinib, alectinib, and brigatinib, on human UDP-glucuronosyltransferases (UGTs) in vitro and to assess their potential DDI risks in vivo. Initial studies demonstrated that all tested ALK inhibitors exhibited a varying extent of inhibition profile on UGTs at starting test concentrations (100 or 60 μM). Subsequent kinetic experiments indicated that alectinib was a selective potent inhibitor for UGT1A4 in a competitive manner with a Ki,u value of 0.07 μM. Ceritinib exhibited a potent noncompetitive inhibition against UGT1A1 and UGT1A7 with Ki,u values of 1.28 and 3.08 μM, respectively, and a competitive inhibition against UGT2B7 with Ki,u of 1.16 μM. Crizotinib and brigatinib demonstrated potent inhibition against UGT2B7 and UGT1A8, respectively. In vitro-in vivo extrapolation (IVIVE) suggested that all four ALK inhibitors have potential for DDIs due to their inhibitory effects on UGTs. Among them, the DDI risks of alectinib and brigatinib were much higher than the FDA standard, which may have an impact on the safety of clinical drug use.