Transport of folates and antifolates in liver.

The characteristics and mechanisms of hepatic transport of folates and antifolate cancer drugs, for example, methotrexate, have been studied in perfused liver, isolated hepatocytes (in both freshly isolated cells and in primary cell culture), and membrane vesicles isolated from the basolateral membrane. Both naturally occurring folates and antifolates are taken up by the perfused liver and secreted into bile by apparently active processes, since these compounds are concentrated in liver and bile compared with the perfusate. Transport of the naturally occurring folate 5-methyltetrahydrofolate in isolated hepatocytes and basolateral membrane vesicles is via cotransport with hydrogen ions, is electroneutral, and is inhibitable by other reduced folates and by methotrexate. Transport of methotrexate is by a multispecific anion carrier, is electrogenic, and is not inhibitable by reduced folates (e.g., 5-methyl- and 5-formyltetrahydrofolate). Thus, the hepatocyte has separate systems for uptake of the naturally occurring, reduced folates and for the 4-amino-substituted antifolates.