Evidence of competitive inhibition of methotrexate absorption by leucovorin calcium in rat small intestine

The effect of leucovorin calcium on the intestinal absorption of methotrexate in rat small intestine was investigated using an in situ rat gut technique. First, the kinetic absorption in situ parameters for methotrexate in solution were obtained: V-m = 21.54 (+/- 2.22) mu M/h; k(m) = 10.51 (+/- 1.08) mu M; k(a) = 0.26 (+/- 0.03) h(-1) and AIC = -188.63. The inhibitory effect of leucovorin calcium in methotrexate intestinal absorption has been investigated by perfusing of 10 mu M methotrexate isotonic solutions containing increasing concentrations of leucovorin calcium (10-500 mu M), and the remaining concentrations of both compounds were measured. A competitive inhibition of methotrexate absorption was detected: the apparent absorption rate constant of the drug decreased as the initial leucovorin calcium concentration increased. Higher leucovorin calcium concentrations, however, did not completely abolish the absorption of the drug (at 500 mu M of leucovorin calcium, only 84% inhibition was observed). Apparent parameters characterizing the absorption of leucovorin calcium in the presence of methotrexate 10 mu M were: V-m = 14.70 (+/- 1.74) mu M; K-mi = 9.43 (+/- 1.59) mu M; k(ai) = 0.28 (+/- 0.02) h(-1); AIC = -191.53). We can concluded that methotrexate and leucovorin calcium compete for the same intestinal carrier system. This means that since leucovorin calcium, because of its ready conversion to other tetrahydrofolic derivatives (McEvoy, 1996. AHFS Drug Information, Bethesda, MD, pp. 751-758), is administered together with methotrexate in order to prevent the hematopoietic and reticuloendothelial toxic effects of folic acid antagonists, using high leucovorin calcium concentrations, when the urine excretion is decreased, could prevent intestinal drug reabsorption and the drug could then be excreted in the feces, thereby decreasing the risk of poisoning. (C) 1997 Elsevier Science B.V.