PMID- 23439660
OWN - NLM
STAT- MEDLINE
DCOM- 20131029
LR  - 20211021
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Linking)
VI  - 41
IP  - 5
DP  - 2013 May
TI  - Induction of xenobiotic receptors, transporters, and drug metabolizing enzymes by 
      oxycodone.
PG  - 1060-9
LID - 10.1124/dmd.112.050401 [doi]
AB  - 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.
FAU - Hassan, Hazem E
AU  - Hassan HE
AD  - Department of Pharmaceutical Sciences, School of Pharmacy, University of 
      Maryland, Baltimore, Maryland, USA.
FAU - Myers, Alan L
AU  - Myers AL
FAU - Lee, Insong J
AU  - Lee IJ
FAU - Mason, Clifford W
AU  - Mason CW
FAU - Wang, Duan
AU  - Wang D
FAU - Sinz, Michael W
AU  - Sinz MW
FAU - Wang, Hongbing
AU  - Wang H
FAU - Eddington, Natalie D
AU  - Eddington ND
LA  - eng
GR  - R01 DK061652/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20130225
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Receptors, Drug)
RN  - 0 (Xenobiotics)
RN  - CD35PMG570 (Oxycodone)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Gene Expression/drug effects
MH  - Humans
MH  - Liver/drug effects/metabolism
MH  - Male
MH  - Oxycodone/*pharmacology
MH  - Polymerase Chain Reaction
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Real-Time Polymerase Chain Reaction
MH  - Receptors, Drug/*biosynthesis/genetics
MH  - Transcriptional Activation
MH  - Xenobiotics/*metabolism
EDAT- 2013/02/27 06:00
MHDA- 2013/10/30 06:00
CRDT- 2013/02/27 06:00
PHST- 2013/02/27 06:00 [entrez]
PHST- 2013/02/27 06:00 [pubmed]
PHST- 2013/10/30 06:00 [medline]
AID - dmd.112.050401 [pii]
AID - 10.1124/dmd.112.050401 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2013 May;41(5):1060-9. doi: 10.1124/dmd.112.050401. Epub 2013 
      Feb 25.