Abstract
Although oxycodone is the most often used opioid agonist, it remains one of the most understudied drugs. We used microarray analysis to better understand the global changes in gene expression in brain tissues of rats repeatedly treated with oxycodone. Many genes were significantly regulated by oxycodone (e.g., Fkbp5, Per2, Rt1.Dα, Slc16a1, and Abcg2). Validation of the microarray data by quantitative real-time-polymerase chain reaction (Q-PCR) indicated that there was a strong significant correlation (r = 0.979, p < 0.0000001) between the Q-PCR and the microarray data. Using MetaCore (a computational platform), many biological processes were identified [e.g., organic anion transport (p = 7.251 × 10−4) and regulation of immune response (p = 5.090 × 10−4)]. Among the regulated genes, Abcg2 mRNA was up-regulated by 2.1-fold, which was further confirmed by immunoblotting (1.8-fold up-regulation). Testing the Abcg2 affinity status of oxycodone using an Abcg2 ATPase assay suggests that oxycodone behaves as an Abcg2 substrate only at higher concentrations (≥500 μM). Furthermore, brain uptake studies demonstrated that oxycodone-induced Abcg2 up-regulation resulted in a significant (p < 0.05) decrease (∼2-fold) in brain/plasma ratios of mitoxantrone. These results highlight markers/mediators of neuronal responses and identify regulatory pathways involved in the pharmacological action of oxycodone. These results also identify genes that potentially modulate tolerance, dependence, immune response, and drug-drug interactions. Finally, our findings suggest that oxycodone-induced up-regulation of Abcg2 enhanced the efflux of the Abcg2 substrate, mitoxantrone, limiting its brain accumulation and resulting in an undesirable drug-drug interaction. Extrapolating these results to other Abcg2 substrates (e.g., daunorubicin and doxorubicin) indicates that the brain uptake of these agents may be affected if they are administered concomitantly with oxycodone.
Footnotes
↵1 Current affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Drake University, Des Moines, Iowa.
↵2 Current affiliation: Department of Pharmaceutical Sciences, College of Notre Dame of Maryland, School of Pharmacy, Baltimore, Maryland.
This study was supported in part by the National Institutes of Health National Center for Research Resources [Grant 1MO1-RR16500]; the University of Maryland; and the Egyptian Ministry of Higher Education.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.029199
-
- MDR
- multidrug resistance protein
- P-gp (Abcb1)
- P-glycoprotein
- MHC
- major histocompatibility complex
- Q-PCR
- quantitative real-time polymerase chain reaction
- Ct
- threshold cycle
- ANOVA
- analysis of variance
- GO
- Gene Ontology
- Gapdh
- glyceraldhyde-3-phosphate dehydrogenase
- Bcrp (Abcg2)
- breast cancer-related protein
- PAGE
- polyacrylamide gel electrophoresis
- PDVF
- polyvinylidene difluoride
- TBS
- Tris-buffered saline
- TBS-T
- TBS Tween 20
- Mrp (Abcc)
- multidrug resistance-associated protein
- MCT
- monocarboxylate transporter
- CNS
- central nervous system
- BBB
- blood-brain barrier
- PK
- pharmacokinetics
- PD
- pharmacodynamics.
- Received June 22, 2009.
- Accepted September 24, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|