Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 96, Issue 9, Pages 2494-2506Publisher
ELSEVIER SCIENCE INC
DOI: 10.1002/jps.20893
Keywords
P-glycoprotein; blood-brain barrier (BBB); Caco-2 cells; distribution; drug transport
Funding
- NIDA NIH HHS [K02 DA019634-01, K02 DA019634] Funding Source: Medline
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Previous studies suggest that P-glycoprotein (P-gp) modulates the PK/PD of many compounds including opioid agonists and chemotherapeutic agents. The objective of this study was to assess the P-gp affinity status of oxycodone, the P-gp expression, and the paclitaxel's tissue distribution in oxycodone-treated rats. P-gp ATPase assay, Caco-2 transepithelial permeability studies, and mdr1a/b (-/-) mice were used to assess the P-gp affinity status of oxycodone. P-gp expression was determined by Western blot analysis while [C-14] paclitaxel's distributions in the liver, kidney, brain, and plasma tissues were determined by liquid scintillation counter. Oxycodone stimulated the P-gp ATPase activity in a concentration-dependant manner. The Caco-2 secretory transport of oxycodone was reduced from 3.64 x 10(-5) to 1.96 x 10(-5) cm/s (p < 0.05) upon preincubation with the P-gp inhibitor, verapamil. The brain levels of oxycodone in mdr1a/b (+/+) were not detectable (< 15 ng/mL) while in mdr1a/b (-/-) the average levels were 115 +/- 39 ng/mL. The P-gp protein levels were increased by 1.3-4.0 folds while paclitaxel's tissue distributions were decreased by 38-90% (p < 0.05) in oxycodone-treated rats. These findings display that oxycodone is a P-gp substrate, induces overexpression of P-gp, and affects paclitaxel's tissue distribution in a manner that may influence its chemotherapeutic activity. 0 2007 Wiley-Liss, Inc.
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