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

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 [ 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.

Mechanisms of P-Glycoprotein Alteration During Anticancer Treatment: Role in the Pharmacokinetic and Pharmacological Effects of Various Substrate Drugs

“…The authors have also found that distribution of intraperitoneally administered paclitaxel to various body compartments is significantly reduced under conditions where P-gp is up-regulated in these tissues (122). As already described, morphine (116,117), oxycodone (122), and fentanyl (123), in addition to most other narcotic analgesics (124), are known to be substrates of P-gp. Therefore, when providing early palliative care for cancer patients, it is crucial to consider alterations in the pharmacokinetics and pharmacological effects of anticancer drugs and narcotic analgesics that are transported by P-gp.…”

“…In rats, 8 days of repeated intraperitoneal injection of oxycodone, a substrate of P-gp, resulted in increases of P-gp protein in several tissues, including the small intestine, liver, kidney, and brain (122). The authors have also found that distribution of intraperitoneally administered paclitaxel to various body compartments is significantly reduced under conditions where P-gp is up-regulated in these tissues (122).…”

Opioids and efflux transporters. Part 1: P-Glycoprotein substrate activity of N-substituted analogs of meperidine

“…Most analogs were substrates for P-gp like verapermil, with the exception of meperidine itself and N-phenylbutyl-N-normeperidine (7). These results show a distinct SAR for P-gp substrate activity in this series as N-phenylalkyl analogs of shorter length (phenethyl (5), phenylpropyl (6)) were substrates.…”

Effects of itraconazole on the pharmacokinetics and pharmacodynamics of intravenously and orally administered oxycodone

“…Moreover, inhibition of brain capillary endothelium P-glycoprotein would increase the penetration of oxycodone to the site of action in the brain and increase the opioid effects. Animal data on the role of P-glycoprotein in the pharmacokinetics of oxycodone is controversial [29,30]. In addition, there are no human data suggesting that oxycodone would be a substrate for P-glycoprotein.…”