Research ArticlesDifferential Involvement of P-Glycoprotein (ABCB1) in Permeability, Tissue Distribution, and Antinociceptive Activity of Methadone, Buprenorphine, and Diprenorphine: In Vitro and In Vivo Evaluation
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INTRODUCTION
The blood–brain barrier (BBB) acts as a regulator of the flux of xenobiotics between the systemic circulation and the central nervous system (CNS). The permeability of drugs across the BBB has been traditionally considered as a factor of molecular weight, protein binding, H-bonding, degree of ionization and lipid solubility.1 However, a convincing body of evidence suggests that the efflux transporter, P-glycoprotein (P-gp, Abcb1), may also modulate drug disposition into the brain.2, 3, 4, 5, 6,
Drug-Stimulated P-gp ATPase Activity
Drug stimulated P-gp ATPase activity was estimated by Pgp-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™ (20 µL) (control, n = 4), verapamil (200 µM) (n = 4), sodium orthovanadate (100 µM) (n = 4), methadone (5–100 µM) (n = 3/conc.), buprenorphine (5–100 µM) (n =
Effect of Modulators on P-gp ATPase Activity
Different concentrations of methadone, buprenorphine, and diprenorphine (Fig. 2) were examined to determine their effects on the P-gp ATPase activity. Each opioid together with a known excess of ATP was incubated with recombinant human P-gp. ATP consumption due to P-gp stimulation by each opioid was detected as a decrease in luminescence, that is, the higher the potency of a compound to stimulate the P-gp ATPase activity, the lower the luminescence signal. The rate of ATP consumption due to
DISCUSSION
The objective of this study was to evaluate the P-gp affinity status of methadone, buprenorphine and diprenorphine to predict P-gp-mediated drug–drug interactions and to determine a better candidate for management of opioid dependence. Classification of opioids or any other compound as a P-gp substrate, nonsubstrate, inducer or inhibitor based on only one assay may be misleading.1,21,23,32 As a result, we used two in vitro (P-gp ATPase and monolayer efflux assays) and two in vivo (opioids'
Acknowledgements
This study was supported in part by University of Maryland Intramural Research grant (A.C.), a Predoctoral Fellowship from the Egyptian Ministry of Higher Education (H.E.H.) and Ralph Shangraw Predoctoral Fellowship from University of Maryland (H.E.H.).
REFERENCES (50)
- et al.
Transporter-mediated permeation of drugs across the blood-brain barrier
J Pharm Sci
(2000) - et al.
The functional role of P-glycoprotein in the blood-brain barrier
J Pharm Sci
(1997) - et al.
Blood-brain barrier efflux transport
J Pharm Sci
(2003) - et al.
The impact of pharmacologic and genetic knockout of P-glycoprotein on nelfinavir levels in the brain and other tissues in mice
J Pharm Sci
(2005) - et al.
Variable modulation of opioid brain uptake by P-glycoprotein in mice
Biochem Pharmacol
(2004) - et al.
Oxycodone induces overexpression of P-glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats
J Pharm Sci
(2007) Drug-drug interaction mediated by inhibition and induction of P-glycoprotein
Adv Drug Deliv Rev
(2003)- et al.
P-glycoprotein-mediated transport of morphine in brain capillary endothelial cells
Biochem Pharmacol
(1999) - et al.
Opioids and efflux transporters. Part 1: P-Glycoprotein substrate activity of N-substituted analogs of meperidine
Bioorg Med Chem Lett
(2007) - et al.
Interaction of nonpeptidic delta agonists with P-glycoprotein by in situ mouse brain perfusion: Liquid chromatography-mass spectrometry analysis and internal standard strategy
J Pharm Sci
(2002)
Synthetic and natural opiates interact with P-glycoprotein in multidrug-resistant cells
J Biol Chem
Methods to compare dissolution profiles and a rationale for wide dissolution specifications for metoprolol tartrate tablets
J Pharm Sci
Simultaneous determination of buprenorphine and its prodrug, buprenorphine propionate, by high-performance liquid chromatography with fluorescence detection: Application to pharmacokinetic studies in rabbits
J Chromatogr B Analyt Technol Biomed Life Sci
Co-administration of sub-antinociceptive doses of oxycodone and morphine produces marked antinociceptive synergy with reduced CNS side-effects in rats
Pain
Structure-activity relationships of P-glycoprotein interacting drugs: Kinetic characterization of their effects on ATPase activity
Biochim Biophys Acta
Methadone: A review of its pharmacokinetic/pharmacodynamic properties
J Pharmacol Toxicol Methods
The role of passive transbilayer drug movement in multidrug resistance and its modulation
J Biol Chem
P-Glycoprotein, a gatekeeper in the blood-brain barrier
Adv Drug Deliv Rev
Investigation of transport mechanism of pentazocine across the blood-brain barrier using the in situ rat brain perfusion technique
J Pharm Sci
The influence of P-glycoprotein on morphine transport in Caco-2 cells. Comparison with paclitaxel
Eur J Pharmacol
Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs
J Pharmacol Exp Ther
Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins
Proc Natl Acad Sci USA
Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A
J Clin Invest
Role of P-glycoprotein in pharmacokinetics: Clinical implications
Clin Pharmacokinet
Dose-ranging study of oxycodone for chronic pain in advanced cancer
J Clin Oncol
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2022, Pharmacology and TherapeuticsCitation Excerpt :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). P-gp is expressed at the apical side of the syncytiotrophoblast (Atkinson, Sibley, Fairbairn, & Greenwood, 2006; Sun et al., 2006) and on the cytotrophoblast, adjacent to the basolateral membrane of the syncytiotrophoblast (Lye et al., 2013), where it promotes transport towards the intervillous space.
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2018, Journal of Pharmaceutical SciencesCitation Excerpt :Methadone slightly inhibited P-gp-mediated transport of rhodamine 123 in a concentration-dependent manner in an accumulation assay,28 but inhibited the efflux of rhodamine 123 with a concentration at 50% inhibition value of 2.6 μg/mL.29 Several studies have shown methadone to be a P-gp substrate by comparing plasma and brain levels in wild-type (mdr1+/+) and P-gp-deficient (mdr1−/−) mice.26,30,31 Methadone is not a substrate of the uptake transporters organic cation transporter (OCT) 1, OCT2, OCT3, organic anion transporting protein (OATP) 1A2, OATP1B1, OATP1B3, or OATP2B1.32