Interactions between cimetidine, nitrofurantoin, and probenecid active transport into rat milk

The purpose of these studies was to further elucidate the active mammary ep ithelial transport processes for the organic cation cimetidine and the orga nic anion nitrofurantoin and to determine which of the identified rat organ ic anion (rOATs) and organic cation (rOCTs) transporters may be responsible for transport of these drugs into milk. Milk-to-serum ratios (M/S) were pr edicted in vitro for nitrofurantoin, p-aminohippurate (PAH), and probenecid , and were compared with the observed M/S values. Groups of six lactating f emale rats received intravenous infusions of cimetidine, nitrofurantoin, PA H, or probenecid alone and with another agent. Steady-state milk and serum concentrations were measured by high performance liquid chromatography. Rev erse transcriptase-polymerase chain reaction was performed to detect rOATs and rOCTs in livers, kidneys, and mammary glands of lactating rats. Nitrofu rantoin and probenecid were actively transported into rat milk with an M/S 100- and 4.7-fold greater than predicted, respectively, but predicted and o bserved M/S values for PAH were similar. The cimetidine infusion did not al ter nitrofurantoin M/S. Nitrofurantoin significantly decreased M/S of cimet idine (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 re sults suggest different secretory transport systems for cimetidine, nitrofu rantoin, and probenecid, but that passive diffusion governs PAH passage int o milk. The products of rOCT1 and rOCT3 might transport these drugs into mi lk.