Research ArticlesOxycodone induces overexpression of P‐glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats
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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A review of pregnancy-induced changes in opioid pharmacokinetics, placental transfer, and fetal exposure: Towards fetomaternal physiologically-based pharmacokinetic modeling to improve the treatment of neonatal opioid withdrawal syndrome
2022, Pharmacology and TherapeuticsCitation Excerpt :On the placental tissues, various drug transporters are expressed that predominantly facilitate opioid transfer from fetus to mother (Fig. 3). Methadone (Tournier et al., 2010; Tournier et al., 2011), oxycodone (Hassan, Myers, Lee, Coop, & Eddington, 2007; Zwisler et al., 2010), fentanyl (Park et al., 2007), and morphine (Callaghan & Riordan, 1993; Sadhasivam et al., 2015) are substrates for P-gp. Buprenorphine is the only opioid discussed in this review that is not transported by P-gp (Hassan, Myers, Coop, & Eddington, 2009), although its metabolite norbuprenorphine is (Tournier et al., 2010).
Nonclinical safety assessment of PF614: A novel TAAP prodrug of oxycodone for chronic pain indication
2019, Regulatory Toxicology and PharmacologyCitation Excerpt :Affinity of opioids to P-glycoprotein (P-gp; ABCB1) plays a key role in affecting the transport, uptake, and PK/PD of many opioid compounds for being P-gp substrates (Zong and Pollack, 2000; Dagenais et al., 2014). In rats, it has been demonstrated that oxycodone is a P-gp substrate and induces overexpression of P-gp to affect tissue distribution of chemotherapeutic agent such as paclitaxel (Hassan et al., 2007). As expected and contrary to outcomes of previous literature on oxycodone, PF614 was found to have low apparent permeability in Caco-2 cells (≤1.17 x 10-6 cm/s) at doses of 0.1 and 10 μM and was not a substrate or inhibitor of P-gp or BCRP transporters.
Simultaneously predict pharmacokinetic interaction of rifampicin with oral versus intravenous substrates of cytochrome P450 3A/P‑glycoprotein to healthy human using a semi-physiologically based pharmacokinetic model involving both enzyme and transporter turnover
2019, European Journal of Pharmaceutical SciencesBrain disposition, metabolism and behavioral effects of the synthetic opioid AH-7921 in rats
2018, NeuropharmacologyCitation Excerpt :In this condition, pharmacokinetic tolerance might also be involved, as indicated by the lower brain levels, with the lower brain-to-plasma ratio of the drug. The brain-to-plasma ratio was also low for the metabolites after the dose challenge; since many of the common opioids are substrates of the efflux transporter P-glycoprotein (Dagenais et al., 2004), it might be speculated that the transporter expression could be induced after chronic treatment, as previously observed for morphine and oxycodone (Aquilante et al., 2000; Hassan et al., 2007). Finally, we can report for the first time the rewarding effect of AH-7921 in the CPP test, an established method for studying the motivational properties of a drug of abuse.
Revisiting Oxycodone Analgesia: A Review and Hypothesis
2017, Anesthesiology Clinics