Summary
We examined the enterohepatic circulation of methotrexate (MTX) in the rat in vivo and determined the effect of the unconjugated bile salt, cholate, on the process. MTX (70 mg/kg body weight) was administered i.v. and the bile salt (1 mM) was delivered through intestinal perfusion. In the control group 38.43%±4% of the administered dose of MTX appeared in bile 2 h after administration of the drug. In the bile salt-treated group 21.4%±3.7% of the administered does of MTX appeared in bile, which was significantly lower (P<0.01) than the proportion in the control group. The liver content of MTX was depressed by 23% in the bile salt-treated group compared with the control group. This study demonstrates, in vivo, the important role that the enterohepatic circulation plays in exposing the small intestine to toxic levels of MTX and shows that the unconjugated bile salt, cholate, inhibits the process.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bleyer WA (1978) The clinical pharmacology of methotrexate. Cancer 41:36–51
Fromm H, Roat JW, Gonzalez V, Sarva RP, Farivar S (1983) Comparative efficiency and side effects of ursodeoxycholic and chenodeoxycholic acids in disolving gallstones. A double blind controlled study. Gastroenterology 85:1257–1264
Henderson GB, Zevely EM (1982) Functional correlation between methotrexate and the general anion transport system of L1210 cells. Biochem Int 4:493–502
Hoffman AF (1976) The enterohepatic circulation of bile acids in man. Clin Gastroenterol 6:3–24
Jolivet J, Cowan KH, Curt GA, et al. (1983) The pharmacology and clinical use of methotrexate. N Engl J Med 308: 1094–1104
Said HM, Hollander D (1986) Inhibitory effect of bile salts on the enterohepatic circulation of methotrexate in the unanesthetized rat. Inhibition of methotrexate intestinal absorption. Cancer Chemother Pharmacol 16:121–124
Said HM, Hollander D, Katez D (1984) Absorption of 5-methyltetrahydrofolate in rat jejunum with intact blood and lymphatic vessels. Biochim Biophys Acta 775:402–408
Said HM, Hollander D, Strum WB (1984) The inhibitory effect of unconjugated bile acids on the enterohepatic circulation of methotrexate. J Pharmacol Exp Ther 231:660–664
Schoenfield LJ, Lachin JM (1981) Chenodiol (chenodeoxycholic acid) for dissolution of gallstones. The national cooperative gallstone study. Ann Intern Med 95:257–282
Shen DD, Azarnoff DL (1978) Clinical pharmacokinetics of amethopterin. Clin Pharmacol 3:1–13
Strum WB, Liem HH (1977) Hepatic uptake, intracellular protein binding and biliary excretion of amethopterin. Biochem Pharmacol 26:1235–1240
Author information
Authors and Affiliations
Additional information
This study was supported by NIH Grant NIADDKD 5P30AM 26657. Donald Griffin is a recipient of an NIH student training award, grant no. 5R25CA 19429-10
Rights and permissions
About this article
Cite this article
Griffin, D., Said, H.M. The enterohepatic circulation of methotrexate in vivo: Inhibition by bile salt. Cancer Chemother. Pharmacol. 19, 40–41 (1987). https://doi.org/10.1007/BF00296253
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00296253