Fluorescent substrates of sister-P-glycoprotein (BSEP) evaluated as markers of active transport and inhibition: evidence for contingent unequal binding sites.
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Wang EJ, Casciano CN, Clement RP, Johnson WW
Fluorescent substrates of sister-P-glycoprotein (BSEP) evaluated as markers of active transport and inhibition: evidence for contingent unequal binding sites.
Pharm Res. 2003 Apr;20(4):537-44.
- PubMed ID
- 12739759 [ View in PubMed]
- Abstract
PURPOSE: Although sister-P-glycoprotein (SPGP, BSEP) is closely related to P-glycoprotein, it is much more selective in distribution and substrate recognition. Moreover, because inhibition or lack of BSEP function has severe consequences including cholestasis, hepatotoxicity, exposure to toxic xenobiotics, and drug interactions, in vitro methods are necessary for quantifying and characterizing specific inhibition of BSEP. Therefore, the objective is to discern a method and quantitatively characterize several example BSEP inhibitors. METHODS: With fluorescent markers having been used successfully to evaluate and quantify inhibition of P-gp-mediated transport, this study evaluates several compounds for specific cell retention caused by BSEP inhibitors. In addition to the several compounds asserted to be BSEP inhibitors, the compounds suggested to be BSEP substrates might also inhibit BSEP competitively. Retained fluorescence of possible BSEP substrates was measured by a flow cell cytometer using transfected cells presenting the BSEP transporter specifically and abundantly. RESULTS: Several compounds were shown to inhibit BSEP active transport of the fluorescent substrates dihydrofluorescein and bodipy. The inhibition potency was quantified (i.e., cyclosporin A IC50 approximately 7 microM), revealing incongruent relative sensitivities among the substrate markers, with H2FDA generally the most sensitive of the series of substrate markers evaluated. CONCLUSIONS: The inconsistent sensitivities of the transport markers (H2FDA and bodipy) were reminiscent of the apparent multiple binding site behaviors observed for P-gp and could indicate opposing and unequal yet interacting binding sites akin to those of P-gp. Nonetheless, notable differences between P-gp and BSEP in marker substrate recognition/transport were apparent despite the observed overlap in xenobiotic recognition and transport. Thus far the most potent inhibitors seem to be cyclosporin, tamoxifen, and valinomycin. There are likely to be much more potent inhibitors, and other substrates also may be more sensitive to inhibition of transport.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Doxorubicin Bile salt export pump Protein Humans UnknownSubstrateDetails Fluorescein Bile salt export pump Protein Humans UnknownSubstrateDetails Glyburide Bile salt export pump Protein Humans UnknownSubstrateInhibitorDetails Ketoconazole Bile salt export pump Protein Humans UnknownInhibitorDetails Paclitaxel Bile salt export pump Protein Humans NoSubstrateInhibitorDetails Progesterone Bile salt export pump Protein Humans UnknownInhibitorDetails Reserpine Bile salt export pump Protein Humans UnknownInhibitorDetails Troglitazone Bile salt export pump Protein Humans UnknownInhibitorDetails Vinblastine Bile salt export pump Protein Humans NoSubstrateInhibitorDetails - Binding Properties
Drug Target Property Measurement pH Temperature (°C) Cyclosporine Bile salt export pump IC 50 (nM) 7500 N/A N/A Details Cyclosporine Bile salt export pump IC 50 (nM) 7800 N/A N/A Details Glyburide Bile salt export pump IC 50 (nM) 146500 N/A N/A Details Glyburide Bile salt export pump IC 50 (nM) 260100 N/A N/A Details Ketoconazole Bile salt export pump IC 50 (nM) 65400 N/A N/A Details Paclitaxel Bile salt export pump IC 50 (nM) 26800 N/A N/A Details Paclitaxel Bile salt export pump IC 50 (nM) 28900 N/A N/A Details Progesterone Bile salt export pump IC 50 (nM) 17300 N/A N/A Details Progesterone Bile salt export pump IC 50 (nM) 224600 N/A N/A Details Reserpine Bile salt export pump IC 50 (nM) 10200 N/A N/A Details Troglitazone Bile salt export pump IC 50 (nM) 66400 N/A N/A Details Vinblastine Bile salt export pump IC 50 (nM) 114700 N/A N/A Details Vinblastine Bile salt export pump IC 50 (nM) 62000 N/A N/A Details - Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
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