The effect of quinidine, used as a probe for the involvement of P‐glycoprotein, on the intestinal absorption and pharmacodynamics of methadone

Kharasch, Evan D.; Hoffer, Christine; Whittington, Dale

doi:10.1111/j.1365-2125.2003.02053.x

Cited by 89 publications

(82 citation statements)

References 57 publications

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“…The plasma concentrations of the concomitant drugs in humans were obtained or assumed on the basis of the previous report (Jamis-Dow et al, 1997;Stewart et al, 2000;Kharasch et al, 2004;Brunton et al, 2005 ] values of quinidine (600 mg/man) after oral administration was 1.17, where the respiratory depressant effects of loperamide were observed. Of note, the dosage of quinidine in this study was relatively higher than the conventional therapeutic dosage (Brunton et al, 2005).…”

Section: Resultsmentioning

confidence: 99%

Retrospective Analysis of P-Glycoprotein–Mediated Drug-Drug Interactions at the Blood-Brain Barrier in Humans

Sugimoto¹,

Hirabayashi²,

Amano³

et al. 2013

Drug Metab Dispos

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To date, the in vitro-in vivo correlation (IVIVC) of P-glycoprotein (P-gp)-mediated drug-drug interaction (DDI) at the blood-brain barrier (BBB) in rats indicated that the cutoff value to significantly affect the brain penetration of digoxin was [I ,unbound /K i ] of 1, where I ,unbound is the unbound plasma concentration of P-gp inhibitors. On the basis of the IVIVC in rats, we speculated that clinically used P-gp inhibitors do not cause DDI at the human BBB, because none of the compounds studied was [I ,unbound /K i ]>1 at therapeutic doses. Recently, positron emission tomography studies with P-gp substrates, such as [ ]loperamide, together with potent P-gp inhibitors, have indicated that increases in the influx rate constant for brain entry were observed in humans. Therefore, we aimed to retrospectively analyze the results of P-gp-mediated DDIs with in vitro P-gp inhibition assays and to confirm the appropriate cutoff value. In vitro P-gp inhibition assays using verapamil, N-desmethyl loperamide, and loperamide as P-gp probe substrates were performed in human multidrug resistance protein 1-expressing LLC-PK1 cells. The efflux ratios decreased in the presence of P-gp inhibitors, and the K i of tariquidar was 10 nmol/L, regardless of probe substrates. Taking the in vitro K i and unbound plasma concentrations in clinical DDI studies together, the criterion [I ,unbound /K i ] of 1 was an appropriate cutoff limit to observe significant P-gp-mediated DDI at the BBB in humans. On the other hand, no significant DDI was observed in cases in which [I ,unbound /K i ] was less than 0.1. This criterion was comparable to the previous IVIVC result in rats.Introduction P-glycoprotein [P-gp; multidrug resistance protein 1 (MDR1)] is a member of the ATP-binding cassette transporters that is encoded by the ABCB1 gene in humans. P-gp is ubiquitously expressed in normal tissues, including the small intestine, liver, kidney, and blood-brain barrier, that are involved in drug absorption, elimination, and disposition (Tsuji et al., 1992;Tsuji, 2002;Chan et al., 2004). A wide range of structurally diverse compounds, including anti-cancer drugs, HIV protease inhibitors, cardioactive drugs, and immunosuppressant agents, can be actively transported by P-gp (Eyal et al., 2009). Recently, the clinical relevance of P-gp-mediated drug-drug interactions (DDIs) has been summarized by the draft guidance published by the US Food and Drug Administration (http://www.fda.gov/downloads/Drugs/Guidance ComplianceRegulatoryInformation/Guidances/UCM292362.pdf). Accordingly, it is important to assess whether drug candidates have potential risks of P-gp-mediated DDI in clinical studies.In the brain capillaries, P-gp is localized at the luminal membrane of the endothelial cells and pumps drugs and xenobiotics out from the brain into the blood. In vivo studies using mdr1a knockout mice indicated that P-gp regulates the brain penetration of several drugs, such as dexamethasone, digoxin, and cyclosporin A (Schinkel et al., 1995). However, current cli...

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Section: Resultsmentioning

confidence: 99%

Retrospective Analysis of P-Glycoprotein–Mediated Drug-Drug Interactions at the Blood-Brain Barrier in Humans

Sugimoto¹,

Hirabayashi²,

Amano³

et al. 2013

Drug Metab Dispos

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“…Coadministration of these inhibitors may result in the alteration of the pharmacokinetics of other drugs that are P-gp substrates (Kharasch et al, 2004;Nakagami et al, 2005). Recent studies have demonstrated that RSP increased the intracellular accumulation of P-gp substrates rhodamine123 (Rh123) and calcein-AM in bovine brain microvessel endothelial cells and MDR1 gene transfected MDCK cells, respectively, indicating that RSP is a potential P-gp inhibitor (Mahar Doan et al, 2002;Bachmeier and Miller, 2005).…”

Section: Introductionmentioning

confidence: 99%

Risperidone and Paliperidone Inhibit P-Glycoprotein Activity In Vitro

Zhu

Wang

Markowitz

et al. 2006

Neuropsychopharmacol

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Risperidone (RSP) and its major active metabolite, 9-hydroxy-risperidone (paliperidone, PALI), are substrates of the drug transporter P-glycoprotein (P-gp). The goal of this study was to examine the in vitro effects of RSP and PALI on P-gp-mediated transport. The intracellular accumulation of rhodamine123 (Rh123) and doxorubicin (DOX) were examined in LLC-PK1/MDR1 cells to evaluate P-gp inhibition by RSP and PALI. Both compounds significantly increased the intracellular accumulation of Rh123 and DOX in a concentrationdependent manner. The IC 50 values of RSP for inhibiting P-gp-mediated transport of Rh123 and DOX were 63.26 and 15.78 mM, respectively, whereas the IC 50 values of PALI were 4100 mM, indicating that PALI is a less potent P-gp inhibitor. Caco-2 and primary cultured rat brain microvessel endothelial cells (RBMECs) were utilized to investigate the possible influence of RSP on intestinal absorption and blood-brain barrier (BBB) transport of coadministered drugs that are P-gp substrates. RSP, 1-50 mM, significantly enhanced the intracellular accumulation of Rh123 in Caco-2 cells by inhibiting P-gp activity with an IC 50 value of 5.87 mM. Following exposure to 10 mM RSP, the apparent permeability coefficient of Rh123 across Caco-2 and RBMECs monolayers was increased to 2.02 and 2.63-fold in the apical to basolateral direction, but decreased to 0.37 and 0.21-fold in the basolateral to apical direction, respectively. These data suggest that RSP and PALI, to a lesser extent, have a potential to influence the pharmacokinetics and hence the pharmacodynamics of coadministered drugs via inhibition of P-gp-mediated transport. However, no human data exist that address this issue. In particular, RSP may interact with its own active metabolite PALI by promoting its brain concentration through inhibiting P-gp-mediated efflux of PALI across endothelial cells of the BBB.

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“…Several opioids have been reported previously in animals and/or humans to be in vitro or in vivo substrates for P-glycoprotein, including loperamide (Wandel et al, 2002;Skarke et al, 2003), morphine (Xie et al, 1999;Wandel et al, 2002;Dagenais et al, 2004), methadone (Dagenais et al, 2004;Kharasch et al, 2004), fentanyl (Wandel et al, 2002;Dagenais et al, 2004), alfentanil (Wandel et al, 2002;Kalvass et al, 2007), and sufentanil (Wandel et al, 2002). Norbuprenorphine has been identified as a substrate for P-gp-mediated efflux by in vitro screening using transfected Madin-Darby canine kidney (MDCK) cells (Tournier et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

P-Glycoprotein Is a Major Determinant of Norbuprenorphine Brain Exposure and Antinociception

Brown

Campbell

Crafford

et al. 2012

J Pharmacol Exp Ther

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Norbuprenorphine is a major metabolite of buprenorphine and potent agonist of , ␦, and opioid receptors. Compared with buprenorphine, norbuprenorphine causes minimal antinociception but greater respiratory depression. It is unknown whether the limited antinociception is caused by low efficacy or limited brain exposure. Norbuprenorphine is an in vitro substrate of the efflux transporter P-glycoprotein (Mdr1), but the role of P-glycoprotein in norbuprenorphine transport in vivo is unknown. This investigation tested the hypothesis that limited norbuprenorphine antinociception results from P-glycoprotein-mediated efflux and limited brain access. Human P-glycoprotein-mediated transport in vitro of buprenorphine, norbuprenorphine, and their respective glucuronide conjugates was assessed by using transfected cells. P-glycoprotein-mediated norbuprenorphine transport and consequences in vivo were assessed by using mdr1a(ϩ/ϩ) and mdr1a(Ϫ/Ϫ) mice. Antinociception was determined by hotwater tail-flick assay, and respiratory effects were determined by unrestrained whole-body plethysmography. Brain and plasma norbuprenorphine and norbuprenorphine-3-glucuronide were quantified by mass spectrometry. In vitro, the net P-glycoproteinmediated efflux ratio for norbuprenorphine was nine, indicating significant efflux. In contrast, the efflux ratio for buprenorphine and the two glucuronide conjugates was unity, indicating absent transport. The norbuprenorphine brain/plasma concentration ratio was significantly greater in mdr1a(Ϫ/Ϫ) than mdr1a(ϩ/ϩ) mice. The magnitude and duration of norbuprenorphine antinociception were significantly increased in mdr1a(Ϫ/Ϫ) compared with mdr1a(ϩ/ϩ) mice, whereas the reduction in respiratory rate was similar. Results show that norbuprenorphine is an in vitro and in vivo substrate of P-glycoprotein. P-glycoprotein-mediated efflux influences brain access and antinociceptive, but not the respiratory, effects of norbuprenorphine.

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The effect of quinidine, used as a probe for the involvement of P‐glycoprotein, on the intestinal absorption and pharmacodynamics of methadone

Cited by 89 publications

References 57 publications

Retrospective Analysis of P-Glycoprotein–Mediated Drug-Drug Interactions at the Blood-Brain Barrier in Humans

Retrospective Analysis of P-Glycoprotein–Mediated Drug-Drug Interactions at the Blood-Brain Barrier in Humans

Risperidone and Paliperidone Inhibit P-Glycoprotein Activity In Vitro

P-Glycoprotein Is a Major Determinant of Norbuprenorphine Brain Exposure and Antinociception

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