Research Articles
Oxycodone induces overexpression of P‐glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats

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ABSTRACT

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 [14C] 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

Section snippets

INTRODUCTION

Opioid analgesics are by far the most efficacious pharmacotherapeutic agents for the management of moderate to severe pain. Opioids produce analgesia by binding to specific opioid receptors (µ, δ, and κ) both within and outside the CNS. Unfortunately, effective management of chronic cancer pain represents a therapeutic challenge since chronic administration of opioids in most cases is accompanied by undesired effects, such as respiratory depression, nausea, vomiting, constipation, tolerance,

Oxycodone‐Stimulated P‐gp ATPase Activity

Oxycodone stimulated P‐gp ATPase activity was estimated by the P‐gp‐GIO assay system (Promega, Madison, WI). This method relies on the ATP dependence of the light‐generating reaction of firefly luciferase. ATP consumption is detected as a decrease in luminescence. In a 96‐well plate, recombinant human P‐gp (25 µg) was incubated with P‐gp‐GIO assay buffer™ (Promega) (20 µL), verapamil (200 µM), sodium orthovanadate (100 µM), or oxycodone (5, 10, 200, 1000, and 2000 µM) (gift from Dr. Coop's

Effect of Oxycodone on P‐gp ATPase Activity

Wide range of oxycodone concentrations were examined for their effects on P‐gp ATPase activity. Each oxycodone concentration together with a known excess of ATP was incubated with recombinant human P‐gp for 40 min. ATP consumption was detected as a decrease in luminescence i.e., the higher the stimulation of the P‐gp ATPase activity, the lower the luminescence signal. The rate of ATP consumption increased in a concentration‐dependant manner and ranged from 7.60 to 113.74 pmol ATP/µg P‐gp/min (

DISCUSSION

Oxycodone has been used effectively for pain management but little is known about its P‐gp affinity status. In addition, there are no data reported on the level of expression of P‐gp upon repeated oxycodone administration. Changes in the level of P‐gp expression may modulate the pharmacokinetics as well as the pharmacodynamics of the concomitantly administered therapeutic agents that are P‐gp substrates. The present study was designed to investigate the P‐gp affinity status of oxycodone, the

Acknowledgements

This study was supported in part by University of Maryland Intramural Research grant, a Predoctoral Fellowship from the Egyptian Ministry of Higher Education (H.E.H.). Part of this study was selected to receive the Eli Lilly PPDM Graduate Student Award H.E.H. at the Annual Meeting of the American Association of Pharmaceutical Scientists (AAPS), San Antonio, Texas, October 29th–November 2nd, 2006.

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