The hepatocellular transport of sulfobromophthalein-glutathione by clofibrate treated, perfused rat liver

The hypolipidemic drug clofibrate is known to affect the hepatic transport of various organic anions including bilirubin, fatty acids and sulfobromophthalein. Changes in the rate of metabolism and/or intracellular transport have been claimed responsible for the effect. To evaluate these possibilities, the transport of sulfobromophthalein-glutathione, a model compound that does not require metabolism for biliary excretion, was studied in perfused livers isolated from clofibrate-treated and control rats. Cytosolic fatty acid binding protein and glutathione S-transferase activity were also measured. Clofibrate treatment significantly increased liver weight; as a result glutathione S-transferase activity (toward 1-chloro-2,4-dinitrobenzene) fell if expressed per gram of liver (4560±420 (SE) vs 7010±260 nmoles/min for clofibrate treated and controls respectively, p<0.002), but was unchanged when expressed per total liver (60.8±6.5 vs 64.6±3.5 μmoles/min for clofibrate and controls p>0.5). Irrespective of how it was expressed fatty acid binding protein was significantly increased by the drug treatment. Steady state sulfobromophthalein-glutathione removal velocity was saturble with increasing concentrations of sulfobromophthalein-glutathione in both control and clofibrate-treated livers. Steady state extraction ratio, as well as Vmax and Km for removal, did not differ between the two groups. In keeping with other observations, these data collectively indicate that the hepatic steady state removal of nonmetabolized compounds is not affected by clofibrate. Because the concomitant decrease in glutathione S-transferase activity only reflects an opposite change in liver weight, it remains to be determined whether clofibrate alters the hepatic transport of sulfobromophthalein and other compounds that are conjugated with glutathione solely by changing their rate of metabolism