In vitro and in vivo hepatic transport of the magnetic resonance imaging contrast agent B22956/1: role of MRP proteins.
The molecular mechanisms of the hepatic transport of B22956/1, a new gadolinium complex from the class of intravascular contrast agents for MRI, which undergoes extensive biliary elimination, were studied. Biliary and urinary elimination of B22956/1 were measured in normal and in mutant MRP2 lacking rats (TR(-)); cellular trafficking of the compound was assessed in wild and MRP1 or MRP2 transfected MDCKII cells. Eight hours after IV injection of B22956/1, 90+/-8% of the dose was recovered in the bile of normal rats. By contrast, in TR(-) rats, the biliary excretion was significantly lower (14+/-3%) while 55+/-9% of the compound was found in urine. In vitro, the cellular accumulation of B22956/1 was significantly lower in both MRP1 and MRP2 transfected cells as compared to wild type MDCKII cells, and the cellular efflux was prevented by the MRP inhibitor MK571, indicating the involvement of both MRP2 and MRP1 in the transport of B22956/1. Due to the distinct cellular localization of the proteins, MRP2 accounts for the biliary and urinary excretion of the compound, while MRP1 prevents cellular accumulation of the MRI agent. B22956/1 may be useful in clinical conditions where a defective biliary transport is present.
Lorusso
Vito
V
Milano Research Center, Bracco Imaging S. p. A., via Egidio Folli 50, 20134 Milano, Italy. vlorusso@bracco.it
Pascolo
Lorella
L
Fernetti
Cristina
C
Visigalli
Massimo
M
Anelli
Pierlucio
P
Tiribelli
Claudio
C
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D001646:Bile / Q000378:metabolism; D001692:Biological Transport; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003287:Contrast Media; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D026901:Membrane Transport Proteins; D008657:Metabolic Clearance Rate; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D051381:Rats; D011922:Rats, Mutant Strains; D014018:Tissue Distribution
D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; D003287:Contrast Media; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009942:Organometallic Compounds; C423013:Abcc2 protein, rat; C440468:B-22956-1; C421109:multidrug resistance-associated protein 1