Inhibition of 5-methyltetrahydrofolic acid transport by amphipathic drugs.
Numerous chemically unrelated drugs after the membrane transport of folate compounds. To investigate drug structure-activity relationships, we measured the effect of amphipathic drugs (that is, compounds with polar-apolar character) on 5-methyltetrahydrofolic acid permeability of human erythrocytes. All drugs tested were inhibitory, but only compounds that exist at least partially in the anionic form were highly active. Ethacrynic acid, sulfinpyrazone, phenylbutazone, sulfasalazine, and furosemide were effective transport inhibitors in micromolar concentrations. In contrast, compounds that are capable of forming cations at physiologic pH, such as chlorpromazine, procaine, tetracaine, and papaverine, were inhibitory only in millimolar concentrations or caused hemolysis before major inhibition was seen. Inhibitory activity correlated with drug dissociation constant (r = 0.87). A double-reciprocal plot analysis of drug effect on 5-methyltetrahydrofolic acid transport showed changes in both Km and Vmax (indicating a mixture of competitive and noncompetitive inhibition) by ethacrynic acid, sulfasalazine, and phlorizin. Inhibitory activity of a series of eight phenoxyacetic derivatives, including ethacrynic acid, correlated highly with measurements of liposolubility (r = 0.87) but only weakly with the Hammet substituent constant (r = 0.56). These results suggest that the effect of amphipathic drugs on 5-methyltetrahydrofolic acid transport is influenced by drug pKa and by the presence of hydrophobic substituents, but is relatively independent of electron-attracting groups.
D000328:Adult; D000838:Anions; D001692:Biological Transport / Q000187:drug effects; D002412:Cations; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D012995:Solubility; D013329:Structure-Activity Relationship; D013763:Tetrahydrofolates / Q000097:blood / Q000378:metabolism*
D000838:Anions; D002412:Cations; D013763:Tetrahydrofolates; C005984:5-methyltetrahydrofolate