EVIDENCE OF COMPETITIVE-INHIBITION OF METHOTREXATE ABSORPTION BY LEUCOVORIN CALCIUM IN RAT SMALL-INTESTINE

The effect of leucovorin calcium on the intestinal absorption of metho trexate in rat small intestine was investigated using an in situ rat g ut technique. First, the kinetic absorption in situ parameters for met hotrexate 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 = -18 8.63. The inhibitory effect of leucovorin calcium in methotrexate inte stinal absorption has been investigated by perfusing of 10 mu M methot rexate isotonic solutions containing increasing concentrations of leuc ovorin calcium (10-500 mu M), and the remaining concentrations of both compounds were measured. A competitive inhibition of methotrexate abs orption was detected: the apparent absorption rate constant of the dru g 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 characterizin g 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 tha t methotrexate and leucovorin calcium compete for the same intestinal carrier system. This means that since leucovorin calcium, because of i ts ready conversion to other tetrahydrofolic derivatives (McEvoy, 1996 . AHFS Drug Information, Bethesda, MD, pp. 751-758), is administered t ogether with methotrexate in order to prevent the hematopoietic and re ticuloendothelial toxic effects of folic acid antagonists, using high leucovorin calcium concentrations, when the urine excretion is decreas ed, 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.