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Drug Metabolism & Disposition

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OtherShort Communication

THE β-d-GLUCOSIDE AND SODIUM-DEPENDENT GLUCOSE TRANSPORTER 1 (SGLT1)-INHIBITOR PHLORIDZIN IS TRANSPORTED BY BOTH SGLT1 AND MULTIDRUG RESISTANCE-ASSOCIATED PROTEINS 1/2

Thomas Walle and U. Kristina Walle
Drug Metabolism and Disposition November 2003, 31 (11) 1288-1291; DOI: https://doi.org/10.1124/dmd.31.11.1288
Thomas Walle
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U. Kristina Walle
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Abstract

Phloridzin, a glucoside of the flavonoid-like polyphenol phloretin, has long been known to be a specific nontransportable inhibitor of the sodium-dependent glucose transporter SGLT1. The objective of this study was to determine whether efflux by multidrug resistance-associated protein (MRP) transporters might have masked the absorption by SGLT1 in previous studies. Various cells used as transport models were incubated with phloridzin (50 μM) in the absence and presence of 50 μM 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK-571), a highly selective MRP1/MRP2 inhibitor, and the cellular uptake of phloridzin was measured by high performance liquid chromatography. The uptake of phloridzin by SGLT1-transfected Chinese hamster ovary (CHO) (G6D3) cells was 1.7-fold higher than that by parent CHO cells (p < 0.01). In the presence of MK-571, the uptake of phloridzin by CHO cells increased 3.7-fold (p < 0.001). MK-571 caused an 8.0-fold increase in the uptake of phloridzin by G6D3 cells (p < 0.0001). Thus, in the absence of MRP1 efflux, transport of phloridzin by SGLT1 was clearly demonstrated. Similar results were obtained for the glycosides of the flavonoids quercetin, genistein, and diosmetin. A significantly lower accumulation of phloridzin in MRP2-transfected Madin-Darby canine kidney (MDCK) cells compared with parent MDCK cells demonstrated that phloridzin was a substrate also for MRP2 (p < 0.05). This conclusion was further strengthened when MK-571 increased the uptake by MRP2-MDCK cells as much as 3.6-fold (p < 0.01). These results demonstrate that phloridzin, in contrast to previous notions, is transported by SGLT1. In addition, they demonstrate that this and other flavonoid glycosides unexpectedly are efficiently effluxed by both MRP1 and MRP2.

Footnotes

  • ↵1 Abbreviations used are: SGLT1, sodium-dependent glucose transporter 1; MRP, multidrug resistance-associated protein; CHO, Chinese hamster ovary; G6D3, SGLT1-transfected CHO cells; MK-571, 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid; MDCK, Madin-Darby canine kidney; BSO, buthionine-[S,R]-sulfoximine; HPLC, high performance liquid chromatography.

  • This study was supported by National Institutes of Health Grant GM55561. It was presented in part at the 2002 American Association of Pharmaceutical Scientists Annual Meeting, Toronto, Ontario, Canada, November 10-14, 2002.

    • Received February 26, 2003.
    • Accepted July 24, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (11)
Drug Metabolism and Disposition
Vol. 31, Issue 11
1 Nov 2003
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THE β-d-GLUCOSIDE AND SODIUM-DEPENDENT GLUCOSE TRANSPORTER 1 (SGLT1)-INHIBITOR PHLORIDZIN IS TRANSPORTED BY BOTH SGLT1 AND MULTIDRUG RESISTANCE-ASSOCIATED PROTEINS 1/2
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OtherShort Communication

THE β-d-GLUCOSIDE AND SODIUM-DEPENDENT GLUCOSE TRANSPORTER 1 (SGLT1)-INHIBITOR PHLORIDZIN IS TRANSPORTED BY BOTH SGLT1 AND MULTIDRUG RESISTANCE-ASSOCIATED PROTEINS 1/2

Thomas Walle and U. Kristina Walle
Drug Metabolism and Disposition November 1, 2003, 31 (11) 1288-1291; DOI: https://doi.org/10.1124/dmd.31.11.1288

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THE β-d-GLUCOSIDE AND SODIUM-DEPENDENT GLUCOSE TRANSPORTER 1 (SGLT1)-INHIBITOR PHLORIDZIN IS TRANSPORTED BY BOTH SGLT1 AND MULTIDRUG RESISTANCE-ASSOCIATED PROTEINS 1/2

Thomas Walle and U. Kristina Walle
Drug Metabolism and Disposition November 1, 2003, 31 (11) 1288-1291; DOI: https://doi.org/10.1124/dmd.31.11.1288
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