Oxycodone induces overexpression of P‐glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats
2007; Elsevier BV; Volume: 96; Issue: 9 Linguagem: Inglês
10.1002/jps.20893
ISSN1520-6017
AutoresHazem E. Hassan, Alan L. Myers, Insong J. Lee, Andrew Coop, Natalie D. Eddington,
Tópico(s)Pharmacogenetics and Drug Metabolism
ResumoABSTRACT 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 [ 14 C] 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 × 10 −5 to 1.96 × 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. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2494–2506, 2007
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