The enterohepatic circulation of methotrexate in vivo: inhibition by bile salt.

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 doses of MTX appeared in bile, which was significantly lower (P less than 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.