Journal
DRUG METABOLISM AND DISPOSITION
Volume 46, Issue 8, Pages 1066-1074Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/dmd.118.081729
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Oligonucleotides represent an expanding class of pharmacotherapeutics in development for various indications. Typically, oligonucleotides are developed with phosphorothioate linkages for the improvement of biologic stability; however, limited data are available on the potential of these molecules to cause drug-drug interactions (DDIs). In this study, four nontherapeutic oligonucleotides with either a phosphodiester or phosphorothioate linkage and partial sequences towards glutathione peroxidase or beta-actin (PD-GP and PD-Ac or PT-GP and PT-Ac, respectively) were evaluated in vitro for their potential to inhibit cytochrome P450 (P450) enzymes and UGP-glucuronosyltransferases (UGTs) in both human liver microsomes (HLMs) and cryopreserved human hepatocytes (CHHs) and to inhibit select transporters in expression systems. PD-GP and PD-Ac had little to no inhibitory effect on any P450 or UGT enzymes in HLMs and CHHs, except for PD-Ac in HLMs for CYP2C19 (IC50 = 29 mu M). Conversely, PT-GP and PT-Ac caused direct inhibition of almost all P450 and UGT enzymes, with CYP1A2 (IC50 values of 0.8-4.2 mu M), CYP2C8 (IC50 values of 1.1-12 mu M), and UGT1A1 (IC50 values of 4.5-5.4 mu M) inhibited to the greatest extent. There was evidence of possible time-dependent inhibition (TDI) of P450 enzymes with PT-GP and PT-Ac for CYP2B6, CYP2C8, CYP2C19, CYP2C9, CYP2D6, and CYP3A4/5; however, this TDI was reversible. In contrast to HLMs, there was little to no direct P450 inhibition by any oligonucleotide in CHHs [except for PD-Ac with CYP2C19 (IC50 = 36 mu M) and TDI by PT-GP with CYP2C8], demonstrating test system-dependent outcomes. Inhibition was observed for the organic anion uptake transporters, including organic anion-transporting polypeptide OATP1B1 and OATP1B3, organic anion transporters OAT1 and OAT3, and organic cation transporter OCT2 (IC50 values of 12-29 mu M), but not OCT1 or the efflux transporters breast cancer resistance protein and P-glycoprotein by the phosphorothioate oligonucleotides.
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