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Role of membrance transport in the pharmacologic action of antifolates.

The property of accumulating and maintaining pharmacologically effective intracellular levels of folate analogs is different among proliferative tissues, both normal and tumorous, in mice. The higher sensitivity of the small intestine compared to bone marrow for folate analogs is related to greater retention of unbound drug and more prolonged inhibition of DNA synthesis in the former. Similar differences favoring greater retention of drug and more prolonged inhibition of DNA synthesis in responsive tumors compared to nonresponsive tumors and small intestine appear to account for the selective antitumor action of these agents in murine tumor models. The observed pharmacokinetic differences among tissues are largely attributable to differences in the structural specificity of carrier-mediated membrane transport of folate analogs.