Sodium dependence of nitrofurantoin active transport across mammary epithelia and effects of dipyridamole, nucleosides, and nucleobases

Purpose. The sodium dependence and effects of nucleoside and nucleobase transport inhibitors were determined to ascertain the role of sodium dependent nucleoside or nucleobase transporters in nitrofurantoin active transport across mammary epithelia. Methods. Five lactating female rats received steady-state intravenous infusions of nitrofurantoin with and without the broad-based inhibitor dipyridamole. In the CIT3 murine model of lactation, C-14-nitrofurantoin basolateral to apical permeability was examined in the presence of varying sodium concentrations, purine and pyrimidine nucleosides and nucleobases, and dipyridamole. Results. Dipyridamole effectively inhibited C-14-nitrofurantoin flux across CIT3 cells, with K-i = 0.78 muM (95% C.I. = 0.11 to 5.3 muM) and significantly decreased the milk-to-serum ratio of nitrofurantoin from 29.2 +/- 5.0 to 11.0 +/- 6.3 without changing systemic clearance. Nitrofurantoin active transport was significantly inhibited by complete sodium replacement. Adenosine and guanosine significantly inhibited nitrofurantoin permeability (54.5 +/- 2.6 (mud/hr)/cm(2) and 50.7 +/- 0.6 (mul/hr)/cm(2), respectively, vs. control 90.5 +/- 4.6 (mul/hr)/cm(2)) but uridine, thymidine, and the nucleobases had no effect. Conclusions. Nitrofurantoin active transport was sodium dependent and inhibited by dipyridamole, adenosine, and guanosine, but known sodium dependent nucleoside or nucleobase transporters were not involved.