Sodium dependence of nitrofurantoin active transport across mammary epithelia and effects of dipyridamole, nucleosides, and nucleobases.
OBJECTIVE
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, 14C-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 14C-nitrofurantoin flux across CIT3 cells, with Ki = 0.78 microM (95% C.I. = 0.11 to 5.3 microM) 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 (microl/hr)/cm2 and 50.7 +/- 0.6 (microl/hr)/cm2, respectively, vs. control 90.5 +/- 4.6 (microl/hr)/cm2) 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.
Gerk
Phillip M
PM
University of Kentucky College of Pharmacy, Division of Pharmaceutical Science Lexington, 40536-0082, USA.
Hanson
Linda
L
Neville
Margaret C
MC
McNamara
Patrick J
PJ
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004176:Dipyridamole / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism*; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008892:Milk / Q000187:drug effects / Q000378:metabolism; D009582:Nitrofurantoin / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011687:Purines / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009705:Nucleosides; D010726:Phosphodiesterase Inhibitors; D011687:Purines; D011743:Pyrimidines; C065171:cif nucleoside transporter; D004176:Dipyridamole; D009582:Nitrofurantoin