Comprehensive in vitro evaluation of the inhibitory effects of relatively high molecular weight peptides on drug-drug interaction-associated four liver transporters and its association with physicochemical properties

In recent years, advances in peptide synthesis have enabled the construction of relatively high molecular weight (Mw; >1 kDa) peptides using various types of amino acids (AAs), including proteinogenic/natural and nonnatural AAs. This advancement helps in obtaining peptides with improved stability, cell membrane permeability, and/or target-binding affinity. However, drug-drug interaction (DDI) information for these peptides remains scarce. Therefore, we focused on relatively high Mw peptides to examine their potential in inhibiting liver transporters, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, P-glycoprotein, and breast cancer resistant protein (BCRP) in vitro. We addressed the inhibitory effects of various types of cyclic peptides containing non-natural AAs and cell-penetrating peptides composed of proteinogenic/natural AAs. Our results demonstrated that several peptides inhibited transport activities, indicating that they can potentially cause DDI. We further evaluated the relationship between their inhibition potency and physicochemical properties (Mw and hydrophobicity or charge of the constituting AA) to characterize the specific physicochemical properties contributing to their inhibition potency. The hydrophobic AA contents of the peptides correlated with the inhibition potencies for all four transporters. Our findings demonstrate the transporter-mediated DDI potential of peptides and the necessity of their evaluation for drug development.