TISSUE PHARMACOKINETICS, INHIBITION OF DNA-SYNTHESIS, AND TUMOR-CELL KILL AFTER HIGH-DOSE METHOTREXATE IN MURINE TUMOR MODELS

  • 1 January 1976
    • journal article
    • research article
    • Vol. 36  (12) , 4672-4678
Abstract
In sarcoma 180 and L1210 [leukemia] ascites tumor models, the initial rate of methotrexate accumulation in tumor cells in the peritoneal cavity and in small intestine (intracellularly) after s.c. doses up to 800 mg/kg, showed saturation kinetics. These results and the fact that initial uptake in these tissues within this dosage range was inhibited to the expected relative extent by the simultaneous administration of leucovorin suggest that carrier mediation and not passive diffusion is the major route of drug entry at these extremely high doses. Maximum accumulation of intracellular drug occurred within 2 h and reached higher levels in small intestine than in tumor cells at the higher dosages. At a 3 mg/kg dose of methotrexate s.c., intracellular exchangeable drug levels persisted more than 4 times longer in L1210 cells than in small intestine, but differences in persistence (L1210 cell vs. gut) diminished markedly with increasing dosage. At 96 mg/kg, the difference in persistence was less than 2-fold. In small intestine and L1210 cells, the duration of inhibition of DNA synthesis at different dosages correlated with the extent to which exchangeable drug was retained. Toxic deaths occurred when inhibition in small intestine lasted longer than 25-30 h. Recovery of synthesis in small intestine and L1210 cells occurred synchronously and only below dosages of 400 mg/kg. Within 24 h after dosages of > 24 mg/kg, the rate of tumor cell loss increased to a point characterized by a single exponential (t1/2 = 8.5 h). The total cell loss, but not the rate of cell loss, was dose dependent.