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An assessment of the in vitro inhibition of cytochrome P450 enzymes (CYP), UDP-glucuronsyltransferases (UGT) and transporters by phosphodiester- or phosphorothioate-linked oligonucleotides

  • Published on May 7, 2018
  • Biologics & Oligonucleotides
  • Drug Transporters
  • Enzyme Inhibition
  • Non-CYP Enzymes
  • Publications
  • White Papers

Faraz Kazmi, Phyllis Yerino, Chase McCoy, Andrew Parkinson, David B Buckley and Brian W Ogilvie

Oligonucleotides represent an expanding class of pharmacotherapeutics in development for various indications. Typically, oligonucleotides are developed with phosphorothioate linkages for the improvement of biological stability; however limited data are available on the potential of these molecules to cause drug-drug interactions (DDIs). In the present study, two non therapeutic oligonucleotides with either phosphodiester (PD-GP and PD-Ac) or phosphorothioate (PT-GP and PT-Ac) linkages were evaluated in vitro for their potential to inhibit P450s and UGTs in both human liver microsomes (HLM) and cryopreserved human hepatocytes (CHH) 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 HLM and CHH except for PD-Ac in HLM 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 0.8-4.2 μM), CYP2C8 (IC50 values 1.1-12 μM) and UGT1A1 (IC50 values 4.5-5.4 μM) inhibited to the greatest extent. There was evidence of possible time-dependent inhibition (TDI) of CYP enzymes with PT-GP and PT-Ac for CYP2B6, CYP2C8, CYP2C19, CYP2C9, CYP2D6 and CYP3A4/5; however, this TDI was reversible. In contrast to HLM, there was little-to-no direct CYP inhibition by any oligonucleotide in CHH (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 OATP1B1, OATP1B3, OAT1, OAT3, and OCT2 (IC50 values 12-29 μM) but not OCT1 or the efflux transporters BCRP and P-gp by the phosphorothioate oligonucleotides.

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