PT  - JOURNAL ARTICLE
AU  - Faraz Kazmi
AU  - Phyllis Yerino
AU  - Chase McCoy
AU  - Andrew Parkinson
AU  - David B. Buckley
AU  - Brian W. Ogilvie
TI  - An Assessment of the In Vitro Inhibition of Cytochrome P450 Enzymes, UDP-Glucuronosyltransferases, and Transporters by Phosphodiester- or Phosphorothioate-Linked Oligonucleotides
AID  - 10.1124/dmd.118.081729
DP  - 2018 Aug 01
TA  - Drug Metabolism and Disposition
PG  - 1066--1074
VI  - 46
IP  - 8
4099  - http://dmd.aspetjournals.org/content/46/8/1066.short
4100  - http://dmd.aspetjournals.org/content/46/8/1066.full
SO  - Drug Metab Dispos2018 Aug 01; 46
AB  - 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 β-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 μM). 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 μM), CYP2C8 (IC50 values of 1.1–12 μM), and UGT1A1 (IC50 values of 4.5–5.4 μM) 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 μM) 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 μM), but not OCT1 or the efflux transporters breast cancer resistance protein and P-glycoprotein by the phosphorothioate oligonucleotides.