Pharmacokinetic basis for differences in methotrexate sensitivity of normal proliferative tissues in the mouse

Following s.c. administration of varying doses of methotrexate (12 to 400 mg/kg) to mice, the drug accumulated more rapidly and to much higher levels in the small intestine in comparison to bone marrow. The persistence of exchangeable levels of drug (i.e. above that presumed to be equal to the dihydrofolate reductase-binding capacity) was also much greater in the small intestine. In addition, the more prolonged persistence of exchangeable drug in the small intestine compared to marrow correlated with a substantially longer duration of inhibition of DNA synthesis ([6-3H]deoxyuridine incorporation) in the former. Earlier recovery of DNA synthesis as a consequence of more rapid loss of drug appears to explain the lower sensitivity of marrow compared to small intestine to the effects of this agent in mice. These studies extend prior studies in our laboratory to the two major host proliferative populations in mice and allow us to propose that the property for accumulating and maintaining pharmacologically effective intracellular levels of folate analogs is differential among all proliferative tissues (tumor and normal) of this animal and probably in higher mammals as well.