Inhibitory effect of unconjugated bile acids on the enterohepatic circulation of methotrexate.
The effect of unconjugated cholic and deoxycholic acids on intestinal and hepatic transport and bile secretion of methotrexate was studied using everted sacs of rat proximal jejunum and isolated perfused rat liver. Cholic and deoxycholic acids competitively inhibit the mucosal-to-serosal transport of methotrexate (Ki, 0.08 and 0.06 mM, respectively). Cholic and deoxycholic acids also decrease intestinal tissue content of methotrexate in a concentration-dependent manner. Structural and functional damage to the intestinal mucosa does not occur in tissue treated with 0.1 mM and lower concentration of deoxycholic acid as assessed by histological studies, transmural potential difference measurements and the release of the cytoplasmic marker enzyme, lactate dehydrogenase. In the isolated liver, cholic and deoxycholic acids inhibit the uptake, retention and biliary secretion of methotrexate. At 1 mM cholic and deoxycholic acids, 72 and 80% inhibition in liver uptake and 93 and 99% inhibition in bile secretion of 1 microM methotrexate are observed, respectively. These studies demonstrate that unconjugated bile acids inhibit the enterohepatic circulation of methotrexate by impairing its intestinal transport and hepatic uptake and retention and biliary secretion.
D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D004764:Enterohepatic Circulation; D007408:Intestinal Absorption / Q000187:drug effects; D007583:Jejunum / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008099:Liver / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D001647:Bile Acids and Salts; D007770:L-Lactate Dehydrogenase; D008727:Methotrexate