Molecular mechanisms for the hepatic uptake of magnetic resonance imaging contrast agents.
The mechanisms were investigated for the hepatic transport of 4 different gadolinium complexes used as contrast agents for magnetic resonance imaging (MRI). In basolateral rat hepatocyte plasma membrane vesicles, Gd-DTPA uptake was indistinguishable from non-specific binding to vesicles; Gd-BOPTA and Gd-EOB-DTPA entered plasma membrane vesicles following a linear, concentration-dependent mechanism up to 1.5 mM of substrate. By contrast, Gd-B 20790 uptake followed a saturative kinetic with an apparent Km of 92 +/- 15 microM and a Vmax of 143 +/- 42 pmol/mg prot/15 sec, and it occurred into an osmotic-sensitive space. Sulfobromophthalein ant taurocholate, but not unconjugated bilirubin inhibited the uptake rate of Gd-B 20790 but not that of the other three compounds. Injection into Xenopus laevis oocytes of 5 ng of human OATP cRNA resulted, after 3 days, in a >/=2-fold stimulation (p < 0.001) of transport of Gd-B 20790 but not of Gd-BOPTA or Gd-EOB-DTPA. Collectively, these data indicate that the hepatic uptake of the MRI contrast agent Gd-B 20790 is a carrier-mediated mechanism operated by OATP while MRI compounds with other chemical structures enter the hepatocyte by other mechanisms.
Pascolo
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Centro Studi Fegato, Department BBCM, University of Trieste, Trieste, 34100, Italy.
Cupelli
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Anelli
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PL
Lorusso
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Visigalli
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M
Uggeri
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F
Tiribelli
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C
D000818:Animals; D027321:Anion Transport Proteins; D001663:Bilirubin / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003287:Contrast Media / Q000737:chemistry / Q000378:metabolism*; D019786:Gadolinium DTPA / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008536:Meglumine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism; D009994:Osmolar Concentration; D012333:RNA, Messenger / Q000008:administration & dosage / Q000235:genetics; D051381:Rats; D013448:Sulfobromophthalein / Q000378:metabolism / Q000494:pharmacology; D013656:Taurocholic Acid / Q000378:metabolism / Q000494:pharmacology; D014982:Xenopus laevis
D027321:Anion Transport Proteins; D002352:Carrier Proteins; D003287:Contrast Media; D009942:Organometallic Compounds; D012333:RNA, Messenger; C118990:gadolinium B 20790; C073590:gadolinium ethoxybenzyl DTPA; D013448:Sulfobromophthalein; C064572:gadobenic acid; D013656:Taurocholic Acid; D008536:Meglumine; D019786:Gadolinium DTPA; D001663:Bilirubin