text: Induction of xenobiotic receptors, transporters, and drug metabolizing enzymes by oxycodone.
  Perturbations of the expression of transporters and drug-metabolizing enzymes (DMEs) by opioids can be the locus of deleterious drug-drug interactions (DDIs). Many transporters and DMEs are regulated by xenobiotic receptors [XRs; e.g., pregnane X receptor (PXR), constitutive androstane receptor (CAR), and Aryl hydrocarbon receptor (AhR)]; however, there is a paucity of information regarding the influence of opioids on XRs. The objective of this study was to determine the influence of oxycodone administration (15 mg/kg intraperitoneally twice daily for 8 days) on liver expression of XRs, transporters, and DMEs in rats. Microarray, quantitative real-time polymerase chain reaction and immunoblotting analyses were used to identify significantly regulated genes. Three XRs (e.g., PXR, CAR, and AhR), 27 transporters (e.g., ABCB1 and SLC22A8), and 19 DMEs (e.g., CYP2B2 and CYP3A1) were regulated (P < 0.05) with fold changes ranging from -46.3 to 17.1. Using MetaCore (computational platform), we identified a unique gene-network of transporters and DMEs assembled around PXR, CAR, and AhR. Therefore, a series of transactivation/translocation assays were conducted to determine whether the observed changes of transporters/DMEs are mediated by direct activation of PXR, CAR, or AhR by oxycodone or its major metabolites (noroxycodone and oxymorphone). Neither oxycodone nor its metabolites activated PXR, CAR, or AhR. Taken together, these findings identify a signature hepatic gene-network associated with repeated oxycodone administration in rats and demonstrate that oxycodone alters the expression of many transporters and DMEs (without direct activation of PXR, CAR, and AhR), which could lead to undesirable DDIs after coadministration of substrates of these transporters/DMEs with oxycodone.
entities.id: T10 T11 T12 T13 T14 T15 T16 T17 T18 T19 T1 T20 T21 T22 T23 T24 T25 T26 T27 T28 T29 T2 T30 T31 T32 T33 T34 T35 T36 T37 T38 T39 T3 T40 T41 T42 T4 T5 T6 T7 T8 T9
entities.type: CHEMICAL CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-N GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y GENE-Y GENE-N GENE-N GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y GENE-Y GENE-N CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
entities.text: oxycodone oxycodone PXR CAR AhR PXR CAR AhR PXR CAR oxycodone AhR PXR CAR AhR xenobiotic receptors XRs pregnane X receptor PXR constitutive androstane receptor CAR noroxycodone Aryl hydrocarbon receptor AhR XRs XRs XRs PXR CAR AhR ABCB1 SLC22A8 oxymorphone CYP2B2 CYP3A1 xenobiotic receptors oxycodone oxycodone oxycodone oxycodone androstane Aryl hydrocarbon