An Assessment of the In Vitro Inhibition of Cytochrome P450 Enzymes, UDP-Glucuronosyltransferases, and Transporters by Phosphodiester- or Phosphorothioate-Linked Oligonucleotides.

Autor: Kazmi F; Sekisui XenoTech LLC, Kansas City, Kansas (F.K., P.Y., C.M., D.B.B., B.W.O.); Janssen Research & Development LLC, Spring House, Pennsylvania (F.K.); XPD Consulting, Shawnee, Kansas (A.P.); and Roivant Sciences, Durham, North Carolina (D.B.B.) fkazmi@its.jnj.com., Yerino P; Sekisui XenoTech LLC, Kansas City, Kansas (F.K., P.Y., C.M., D.B.B., B.W.O.); Janssen Research & Development LLC, Spring House, Pennsylvania (F.K.); XPD Consulting, Shawnee, Kansas (A.P.); and Roivant Sciences, Durham, North Carolina (D.B.B.)., McCoy C; Sekisui XenoTech LLC, Kansas City, Kansas (F.K., P.Y., C.M., D.B.B., B.W.O.); Janssen Research & Development LLC, Spring House, Pennsylvania (F.K.); XPD Consulting, Shawnee, Kansas (A.P.); and Roivant Sciences, Durham, North Carolina (D.B.B.)., Parkinson A; Sekisui XenoTech LLC, Kansas City, Kansas (F.K., P.Y., C.M., D.B.B., B.W.O.); Janssen Research & Development LLC, Spring House, Pennsylvania (F.K.); XPD Consulting, Shawnee, Kansas (A.P.); and Roivant Sciences, Durham, North Carolina (D.B.B.)., Buckley DB; Sekisui XenoTech LLC, Kansas City, Kansas (F.K., P.Y., C.M., D.B.B., B.W.O.); Janssen Research & Development LLC, Spring House, Pennsylvania (F.K.); XPD Consulting, Shawnee, Kansas (A.P.); and Roivant Sciences, Durham, North Carolina (D.B.B.)., Ogilvie BW; Sekisui XenoTech LLC, Kansas City, Kansas (F.K., P.Y., C.M., D.B.B., B.W.O.); Janssen Research & Development LLC, Spring House, Pennsylvania (F.K.); XPD Consulting, Shawnee, Kansas (A.P.); and Roivant Sciences, Durham, North Carolina (D.B.B.).
Jazyk: angličtina
Zdroj: Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2018 Aug; Vol. 46 (8), pp. 1066-1074. Date of Electronic Publication: 2018 May 07.
DOI: 10.1124/dmd.118.081729
Abstrakt: 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 (IC 50 = 29 μ M). Conversely, PT-GP and PT-Ac caused direct inhibition of almost all P450 and UGT enzymes, with CYP1A2 (IC 50 values of 0.8-4.2 μ M), CYP2C8 (IC 50 values of 1.1-12 μ M), and UGT1A1 (IC 50 values of 4.5-5.4 μ 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 (IC 50 = 36 μ 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 (IC 50 values of 12-29 μ M), but not OCT1 or the efflux transporters breast cancer resistance protein and P-glycoprotein by the phosphorothioate oligonucleotides.
(Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze: MEDLINE
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