Multidrug Resistance Protein 2 Is an Important Determinant of Paclitaxel Pharmacokinetics

Lagas, Jurjen S.; Vlaming, Maria L. H.; Tellingen, Olaf van; Wagenaar, Els; Jansen, Robert S.; Rosing, Hilde; Beijnen, Jos H.; Schinkel, Alfred H.

doi:10.1158/1078-0432.ccr-06-1352

Cited by 89 publications

(91 citation statements)

References 27 publications

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“…Using cells overexpressing mouse and human P-gp paclitaxel was classified as a strong substrate (Schellens et al, 2000;Bardelmeijer et al, 2002). These findings were confirmed using mdr1a/1b(Ϫ/Ϫ) mice (Lagas et al, 2006) and WT mice cotreated with the P-gp inhibitor cyclosporin A (van Asperen et al, 1998), which showed significantly higher …”

Section: Discussionmentioning

confidence: 81%

“…It has been demonstrated that knockout mice are a good model to study the influence of transport proteins on the pharmacokinetics of drugs (Schinkel et al, 1995(Schinkel et al, , 1997Lagas et al, 2006). To evaluate the relevance of the in vitro findings for the in vivo situation brain and plasma concentrations of sorafenib in mdr1a/1b(Ϫ/Ϫ) and wild-type (WT) mice were determined.…”

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confidence: 99%

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In Vitro to In Vivo Comparison of the Substrate Characteristics of Sorafenib Tosylate toward P-Glycoprotein

Gnoth¹,

Sandmann²,

Engel³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Sorafenib (Nexavar) is a novel oral Raf kinase and vascular endothelial growth factor receptor inhibitor. Most anticancer drugs are substrates for ATP-binding cassette efflux pumps especially for P-glycoprotein (P-gp). To evaluate the influence of P-gp on the pharmacokinetics of sorafenib substrate properties for this transporter were investigated. Therefore, permeability of sorafenib across Caco-2 and P-gp-overexpressing cells was determined. To determine the in vivo relevance of these in vitro findings, pharmacokinetics of sorafenib in mdr1a/1b(؊/؊) and wild-type (WT) mice was studied. Sorafenib is highly permeable and exhibits a slight efflux across Caco-2 cells. In P-gp-overexpressing cells, a small concentration-dependent efflux was observed, which was completely blocked by the addition of ivermectin. In mdr1a/1b(؊/؊) and WT mice, unchanged compound represented by far the majority of radioactivity in plasma. After intravenous and oral administration, brain/plasma concentration ratios in mdr1a/1b(؊/؊) mice were 1.3-to 1.5-fold higher than those in WT mice. However, after intravenous or oral administration, plasma concentrations were similar in both mouse strains. In conclusion, sorafenib is highly permeable and a weak P-gp substrate in vitro. These findings were confirmed by the small factor of 1.3 to 1.5 observed for the brain/plasma ratios in mdr1a/1b(؊/؊) versus WT mice in vivo. Based on these in vitro and in vivo results, it is unlikely that P-gp has a major effect on the plasma concentrations of sorafenib in humans. Because of the high permeability and low P-gp-mediated transport, sorafenib might be able to cross the blood-brain barrier and target tumors within the brain.

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Section: Discussionmentioning

confidence: 81%

mentioning

confidence: 99%

In Vitro to In Vivo Comparison of the Substrate Characteristics of Sorafenib Tosylate toward P-Glycoprotein

Gnoth¹,

Sandmann²,

Engel³

et al. 2010

Drug Metab Dispos

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“…We previously showed the value of knockout mice in studying the role of ABCB1 (P-glycoprotein, P-gp) and/or ABCC2 (multidrug resistance protein 2, Mrp2) in PTX pharmacokinetics (13,14). We further aimed to better understand the impact of the Oatp1a/1b transporters at different systemic exposure levels of the anticancer drugs PTX and MTX, by testing different dosages.…”

Section: ) As the Variousmentioning

confidence: 99%

High Impact of Oatp1a/1b Transporters on In Vivo Disposition of the Hydrophobic Anticancer Drug Paclitaxel

Steeg

Esch

Wagenaar

et al. 2011

Clinical Cancer Research

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Purpose: Organic anion-transporting polypeptides (OATP) mediate the cellular uptake of a broad range of drugs. The hydrophobic anticancer drug, paclitaxel (PTX), was recently identified as a substrate for OATP1B3 in vitro. We investigated the role of Oatp1a/1b transporters in the pharmacokinetics of PTX in vivo, as well as their impact at different dose levels of PTX and methotrexate (MTX).Experimental Design: Recently generated Slco1a/1b À/À (lacking all Oatp1a/1b transporters) and wildtype mice were intravenously dosed with 2, 10, or 50 mg/kg of PTX, or with 10, 50, or 500 mg/kg of MTX, and plasma and tissue drug concentrations were measured.Results: In spite of its hydrophobicity, PTX systemic exposure (at 10 mg/kg) was increased by greater than 2-fold in Slco1a/1b À/À mice compared with wild-type, whereas PTX liver uptake was reduced by about 2-fold. Oatp1a/1b transporters displayed a high impact on PTX and MTX pharmacokinetics over a broad dose range. For MTX, even at 500 mg/kg, saturation of Oatp1a/1b was not observed, with a 3.4-fold increase in plasma and 30-fold decrease in liver levels in Slco1a/1b À/À mice compared with wild-type.Although beginning saturation of Oatp1a/1b was observed at the highest dose of PTX, plasma levels in Slco1a/1b À/À mice were still 1.7-fold increased and liver levels 1.5-fold decreased compared with wild-type.Conclusion: Oatp1a/1b transporters play a pronounced role in determining plasma levels and tissue distribution of MTX and PTX, thus affecting even highly hydrophobic drugs. Variation in OATP1A/1B transporter activity, due to genetic variation, inhibition, and/or tumor expression might affect toxicity and therapeutic efficacy of these anticancer drugs.

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“…Because we recently demonstrated that hepatobiliary excretion of paclitaxel in the mouse is almost exclusively dependent on Mrp2 (Lagas et al, 2006), we tried to stimulate biliary paclitaxel excretion in mice by the coadministration of either diclofenac or benzbromarone. However, we were unable to show any in vivo stimulation (J. S. Lagas and A. H. Schinkel, unpublished data).…”

Section: Downloaded Frommentioning

confidence: 99%

“…To date, several compounds, e.g., probenecid, sulfinpyrazone, and sulfanitran, have been shown to stimulate the MRP2-mediated transport of lipophilic amphipathic drugs (Huisman et al, 2002;Zelcer et al, 2003). Stimulation of MRP2-mediated transport can be of interest, because we recently demonstrated in vivo that Mrp2 is an important determinant for biliary excretion and thereby pharmacokinetics of the lipophilic amphipathic anticancer drug paclitaxel (Lagas et al, 2006 GlaxoSmithKline (Uxbridge, Middlesex, UK) kindly provided Elacridar (GF120918). The BCRP/Bcrp1 inhibitor Ko143 was described previously (Allen et al, 2002).…”

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confidence: 99%

Transport of Diclofenac by Breast Cancer Resistance Protein (ABCG2) and Stimulation of Multidrug Resistance Protein 2 (ABCC2)-Mediated Drug Transport by Diclofenac and Benzbromarone

Lagas

Kruijssen²,

Wetering³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Diclofenac is an important analgesic and anti-inflammatory drug, widely used for treatment of postoperative pain, rheumatoid arthritis, and chronic pain associated with cancer. Consequently, diclofenac is often used in combination regimens and undesirable drug-drug interactions may occur. Because many drug-drug interactions may occur at the level of drug transporting proteins, we studied interactions of diclofenac with apical ATP-binding cassette (ABC) multidrug efflux transporters. Using Madin-Darby canine kidney (MDCK)-II cells transfected with human P-glycoprotein (P-gp; MDR1/ABCB1), multidrug resistance protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2) and murine Bcrp1, we found that diclofenac was efficiently transported by murine Bcrp1 and moderately by human BCRP but not by P-gp or MRP2. Furthermore, in Sf9-BCRP membrane vesicles diclofenac inhibited transport of methotrexate in a concentration-dependent manner. We next used MDCK-II-MRP2 cells to study interactions of diclofenac with MRP2-mediated drug transport. Diclofenac stimulated paclitaxel, docetaxel, and saquinavir transport at only 50 M. We further found that the uricosuric drug benzbromarone stimulated MRP2 at an even lower concentration, having maximal stimulatory activity at only 2 M. Diclofenac and benzbromarone stimulated MRP2-mediated transport of amphipathic lipophilic drugs at 10-and 250-fold lower concentrations, respectively, than reported for other MRP2 stimulators. Because these concentrations are readily achieved in patients, adverse drug-drug interactions may occur, for example, during cancer therapy, in which drug concentrations are often critical and stimulation of elimination via MRP2 may result in suboptimal chemotherapeutic drug concentrations. Moreover, stimulation of MRP2 activity in tumors may lead to increased efflux of chemotherapeutic drugs and thereby drug resistance.Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits potent analgesic and anti-inflammatory properties and is extensively used to treat postoperative pain, rheumatoid arthritis, osteoarthritis, and acute gouty arthritis (Davies and Anderson, 1997). Diclofenac is also widely used to treat pain associated with cancer, and treatment combinations of diclofenac with chemotherapeutic drugs are common. In addition, preclinical evidence is accumulating that NSAIDs, including diclofenac, have beneficial effects as adjuvant therapy in treatment of some types of cancer (Crokart et al., 2005;Johnsen et al., 2005). Due to this widespread co-use of drugs, interactions of NSAIDs with chemotherapeutic drugs can result in unexpected toxicities or failure of chemotherapy. For example, NSAIDs are known to restrict plasma clearance of methotrexate (MTX). When MTX is used at high-dose regimens for cancer treatment, interactions with NSAIDs can result in severe toxicity, with sometimes fatal outcome (Thyss et al., 1986). In a recent study, using human kidney slides, it was demonstrated that diclofenac and its acyl-glucuronide c...

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Multidrug Resistance Protein 2 Is an Important Determinant of Paclitaxel Pharmacokinetics

Cited by 89 publications

References 27 publications

In Vitro to In Vivo Comparison of the Substrate Characteristics of Sorafenib Tosylate toward P-Glycoprotein

In Vitro to In Vivo Comparison of the Substrate Characteristics of Sorafenib Tosylate toward P-Glycoprotein

High Impact of Oatp1a/1b Transporters on In Vivo Disposition of the Hydrophobic Anticancer Drug Paclitaxel

Transport of Diclofenac by Breast Cancer Resistance Protein (ABCG2) and Stimulation of Multidrug Resistance Protein 2 (ABCC2)-Mediated Drug Transport by Diclofenac and Benzbromarone

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