Influence of hypotonic stress on the biliary excretion of doxorubicin in Wistar and TR- rats.
In tumor cells, doxorubicin (DOX) is excreted by P-glycoprotein (P-gp) and the multidrug resistance-associated protein (mrp). Both transporters might also be involved in cellular regulatory volume decrease (RVD). To study the hepatobiliary excretion of DOX during RVD, isolated livers of Wistar and multidrug resistance-associated protein 2 (mrp2)-deficient TR- rats were first perfused with an isotonic and later with a hypotonic medium. In both rat strains, DOX is effectively excreted into the bile. Within 30 minutes, the biliary excretion of DOX-derived fluorescence steadily increased to 1.1+/-0.11 and 0.84+/-0.05 nmoles/min . g liver in Wistar and TR- rats, respectively. Under hypotonic conditions, DOX excretion followed the biphasic-increase in bile flow. Excretion was increased to 136+/-19% and 176+/-9% (first peak) and to 141+/-11% and 157+/-14% (second peak) in Wistar and TR- rats, respectively. Our data show that in the liver of both strains, exposure to a hypotonic medium stimulates DOX excretion, presumably by activation of P-gp and mrp2 during RVD.
Gaugg
M
M
Department of Pathophysiology, University of Vienna, AKH, Austria.
Haslmayer
P
P
Jäger
W
W
Thalhammer
T
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D001646:Bile / Q000187:drug effects / Q000502:physiology; D001659:Biliary Tract / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D004317:Doxorubicin / Q000493:pharmacokinetics*; D006982:Hypertonic Solutions; D008099:Liver / Q000378:metabolism*; D008297:Male; D009997:Osmotic Pressure; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D006982:Hypertonic Solutions; D004317:Doxorubicin; D011188:Potassium