Oxycodone induces overexpression of P-glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats.
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 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.
Hassan
Hazem E
HE
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, Maryland 21201, USA.
Myers
Alan L
AL
Lee
Insong J
IJ
Coop
Andrew
A
Eddington
Natalie D
ND
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000701:Analgesics, Opioid / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001693:Biological Transport, Active / Q000502:physiology; D018938:Caco-2 Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D004361:Drug Tolerance; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010098:Oxycodone / Q000378:metabolism / Q000494:pharmacology*; D017239:Paclitaxel / Q000493:pharmacokinetics*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013056:Spectrophotometry, Ultraviolet; D014018:Tissue Distribution; D015854:Up-Regulation / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D000972:Antineoplastic Agents, Phytogenic; D002121:Calcium Channel Blockers; D010098:Oxycodone; D014700:Verapamil; D000251:Adenosine Triphosphatases; D017239:Paclitaxel