Interactions between cimetidine, nitrofurantoin, and probenecid active transport into rat milk.
The purpose of these studies was to further elucidate the active mammary epithelial transport processes for the organic cation cimetidine and the organic anion nitrofurantoin and to determine which of the identified rat organic anion (rOATs) and organic cation (rOCTs) transporters may be responsible for transport of these drugs into milk. Milk-to-serum ratios (M/S) were predicted in vitro for nitrofurantoin, p-aminohippurate (PAH), and probenecid, and were compared with the observed M/S values. Groups of six lactating female rats received intravenous infusions of cimetidine, nitrofurantoin, PAH, or probenecid alone and with another agent. Steady-state milk and serum concentrations were measured by high performance liquid chromatography. Reverse transcriptase-polymerase chain reaction was performed to detect rOATs and rOCTs in livers, kidneys, and mammary glands of lactating rats. Nitrofurantoin and probenecid were actively transported into rat milk with an M/S 100- and 4.7-fold greater than predicted, respectively, but predicted and observed M/S values for PAH were similar. The cimetidine infusion did not alter nitrofurantoin M/S. Nitrofurantoin significantly decreased M/S of cimetidine (26.6 +/- 4.9 versus 17.7 +/- 5.6). Probenecid did not alter the M/S of nitrofurantoin, or PAH, but increased the M/S of cimetidine from 15.5 +/- 3.6 to 21.5 +/- 7.7. Of the six transporter genes, evidence of expression in lactating rat mammary tissue was found for only rOCT1 and rOCT3. The results suggest different secretory transport systems for cimetidine, nitrofurantoin, and probenecid, but that passive diffusion governs PAH passage into milk. The products of rOCT1 and rOCT3 might transport these drugs into milk.
Gerk
P M
PM
University of Kentucky College of Pharmacy, Division of Pharmaceutical Sciences, Lexington, Kentucky 40536-0082, USA.
Oo
C Y
CY
Paxton
E W
EW
Moscow
J A
JA
McNamara
P J
PJ
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D027321:Anion Transport Proteins; D001693:Biological Transport, Active; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D002927:Cimetidine / Q000493:pharmacokinetics*; D005260:Female; D015870:Gene Expression; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008892:Milk / Q000378:metabolism*; D009582:Nitrofurantoin / Q000493:pharmacokinetics*; D009928:Organ Specificity; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; D011339:Probenecid / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015262:Xenobiotics / Q000493:pharmacokinetics*
D000199:Actins; D027321:Anion Transport Proteins; D002352:Carrier Proteins; D008565:Membrane Proteins; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; C100590:Slc22a2 protein, rat; D015262:Xenobiotics; C114338:organic anion transport protein 3; D002927:Cimetidine; D009582:Nitrofurantoin; D011339:Probenecid