Transport of Ethinylestradiol Glucuronide and Ethinylestradiol Sulfate by the Multidrug Resistance Proteins MRP1, MRP2, and MRP3

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...

Section: Discussionmentioning

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. 2009

“…Thus a structurally diverse array of compounds, including cannabinoid type 1 (CB1) receptor antagonists (e.g., rimonabant), ethinyl estradiol conjugates, sulfinpyrazone, indomethacin, and chalcogenopyrylium dyes have been reported to modulate organic anion transport by MRP2 (and MRP3) in a complex fashion (Bakos et al, 2000;Bodo et al, 2003;Zelcer et al, 2003;Chu et al, 2004;Gerk et al, 2004;Wittgen et al, 2011;Myette et al, 2013). To explain the biphasic response to some modulators, it has been proposed that the transporter contains both a transport site and an allosteric modulatory site whereby the modulator stimulates the transporter allosterically at low probe (E 2 17bG) concentrations and competes for the E 2 17bG binding site at higher concentrations Bodo et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Cysteinyl Leukotriene Receptor 1/2 Antagonists Nonselectively Modulate Organic Anion Transport by Multidrug Resistance Proteins (MRP1-4)

Csandl¹,

Conseil²,

Cole³

2016

Active efflux of both drugs and organic anion metabolites is mediated by the multidrug resistance proteins (MRPs). MRP1 (ABCC1), MRP2 (ABCC2), MRP3 (ABCC3), and MRP4 (ABCC4) have partially overlapping substrate specificities and all transport 17b-estradiol 17-(b-D-glucuronide) (E 2 17bG). The cysteinyl leukotriene receptor 1 (CysLT 1 R) antagonist MK-571 inhibits all four MRP homologs, but little is known about the modulatory effects of newer leukotriene modifiers (LTMs). Here we examined the effects of seven CysLT 1 R-and CysLT 2 R-selective LTMs on E 2 17bG uptake into MRP1-4-enriched inside-out membrane vesicles. Their effects on uptake of an additional physiologic solute were also measured for MRP1 [leukotriene C 4 (LTC 4 )] and MRP4 [prostaglandin E 2 (PGE 2 )]. The two CysLT 2 R-selective LTMs studied were generally more potent inhibitors than CysLT 1 R-selective LTMs, but neither class of antagonists showed any MRP selectivity. For E 2 17bG uptake, LTM IC 50 s ranged from 1.2 to 26.9 mM and were most comparable for MRP1 and MRP4. The LTM rank order inhibitory potencies for E 2 17bG versus LTC 4 uptake by MRP1, and E 2 17bG versus PGE 2 uptake by MRP4, were also similar. Three of four CysLT 1 R-selective LTMs also stimulated MRP2 (but not MRP3) transport and thus exerted a concentration-dependent biphasic effect on MRP2. The fourth CysLT 1 R antagonist, LY171883, only stimulated MRP2 (and MRP3) transport but none of the MRPs were stimulated by either CysLT 2 R-selective LTM. We conclude that, in contrast to their CysLTR selectivity, CysLTR antagonists show no MRP homolog selectivity, and data should be interpreted cautiously if obtained from LTMs in systems in which more than one MRP is present.

“…Chu et al (2004) have identified ethinylestradiol glucuronide as a higher affinity substrate for ABCC3 than ABCC2. Further evidence implicating Abcc3 as the major transporter of glucuronide conjugates stems from studies in Abcc3 knockout mice, which exhibit significant hepatic retention of acetaminophen-glucuronide compared with wild-type animals without alterations to Abcc2 protein levels (Manautou et al, 2005).…”

Section: Ezetimibe Disposition Is Altered In Experimental Nashmentioning

confidence: 99%

Molecular Mechanism of Altered Ezetimibe Disposition in Nonalcoholic Steatohepatitis

Hardwick¹,

Fisher²,

Street³

et al. 2012

ABSTRACT:Ezetimibe (EZE) lowers serum lipid levels by blocking cholesterol uptake in the intestine. Disposition of EZE and its pharmacologically active glucuronide metabolite (EZE-GLUC) to the intestine is dependent on hepatobiliary efflux. Previous studies suggested that hepatic transporter expression and function may be altered during nonalcoholic steatohepatitis (NASH). The purpose of the current study was to determine whether NASH-induced changes in the expression and function of hepatic transporters result in altered disposition of EZE and EZE-GLUC. Rats fed a methionine-and choline-deficient (MCD) diet for 8 weeks were administered 10 mg/kg EZE either by intravenous bolus or oral gavage. Plasma and bile samples were collected over 2 h followed by terminal urine and tissue collection. EZE and EZE-GLUC concentrations were determined by liquid chromatography-tandem mass spectrometry. The sinusoidal transporter Abcc3 was induced in MCD rats, which correlated with increased plasma concentrations of EZE-GLUC, regardless of dosing method. Hepatic expression of the biliary transporters Abcc2 and Abcb1 was also increased in MCD animals, but the biliary efflux of EZE-GLUC was slightly diminished, whereas biliary bile acid concentrations were unaltered. The cellular localization of Abcc2 and Abcb1 appeared to be internalized away from the canalicular membrane in MCD livers, providing a mechanism for the shift to plasma drug efflux. The combination of induced expression and altered localization of efflux transporters in NASH shifts the disposition profile of EZE-GLUC toward plasma retention away from the site of action. This increased plasma retention of drugs in NASH may have implications for the pharmacological effect and safety of numerous drugs.