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.

Active transport of nitrofurantoin into rat milk.

Most xenobiotics are transferred into milk by passive diffusion; however, some drugs have been reported to accumulate in milk as a result of active transport. In the present study, lactating Sprague Dawley rats were used to characterize the transfer of nitrofurantoin into milk. The observed milk to serum concentration ratio (M/S) of 31.1+/-4.0 was 100 times higher than the M/S predicted by diffusion (0.3+/-0.1), indicative of an active transfer into milk. Randomized crossover infusions of nitrofurantoin (0.5mg/h) in the absence and presence of a cimetidine infusion regimen (15mg/h) resulted in the corresponding mean M/S of 29.5+/-5.4 vs. 30.7+/-5.0 and systemic clearance (Cls) of 2.7+/-0.7 vs. 2.2+/-0.4 L/h/kg, respectively. Nitrofurantoin infusions (0.5mg/h) in the absence and presence of a higher cimetidine infusion regimen (30mg/h) resulted in the corresponding mean values for M/S of 23.0+/-7.7 vs. 19.8+/-5.9 and Cls of 2.8+/-0.4 vs. 1.4+/-0.4L/h/kg, respectively. Only the decrease in Cls at the higher cimetidine infusion was statistically significant. These observations provide evidence that nitrofurantoin is actively transported into rat milk by a transporter that is not inhibited by cimetidine. These data suggest the presence of at least two distinct mammary epithelial transporter systems, one that transports organic cations (e.g., cimetidine) and another for anions (e.g., nitrofurantoin).

Active transport of cimetidine into human milk.

Most xenobiotics are transferred from blood into breast milk by passive diffusion. However, an active transport mechanism has been speculated for cimetidine, and the purpose of this study was to characterize cimetidine transfer into human milk. Twelve healthy lactating volunteers received single oral doses of 100, 600, and 1200 mg cimetidine in a randomized, crossover design on 3 different days. Blood and milk specimens were collected and assayed for cimetidine. In vitro measurements, including skim to whole milk concentration ratio, milk pH, and free fractions in serum and milk were used for a diffusion model prediction of milk to serum concentration ratio of cimetidine; the mean milk/serum ratio (+/- SD) was 1.05 +/- 0.18. The observed milk/serum ratio (5.77 +/- 1.24) was 5.5 times higher than the milk/serum ratio predicted by diffusion. The observed milk/serum ratio for the three dosing regimens were not significantly different from one another. Time of peak concentration (tmax) in milk (3.3 +/- 0.7 hours) displayed a delay compared with serum tmax (1.7 +/- 0.6 hours). Oral clearance for 1200 mg cimetidine dose (0.47 +/- 0.11 L/hr/kg) was significantly lower compared with oral clearance values for 100 and 600 mg cimetidine doses (0.59 +/- 0.11 and 0.57 +/- 0.13 L/hr/kg, respectively). The maternal dose of cimetidine ingested by a suckling infant based on body weight was estimated to be 6.7%, which appears to be safe under normal conditions. This study provides the first definitive evidence of an active transport system for drug transfer into human milk, which may have broader consequences for the suckling infant.

Pharmacokinetics in lactating women: prediction of alprazolam transfer into milk.

1. Alprazolam, a triazolobenzodiazepine, is extensively prescribed for the treatment of anxiety disorders, which predominantly affect women of child-bearing age. The purpose of the present study was to assess the pharmacokinetics of alprazolam and its two hydroxylated metabolites: 4-hydroxy-alprazolam and alpha-hydroxy-alprazolam in lactating human volunteers and to test the predictability of four recently reported models for drug transfer into milk based on physicochemical properties. 2. Multiple milk and serum samples in eight lactating subjects were collected up to 36 h following single oral doses of 0.5 mg alprazolam; suckling of the infant was discontinued after drug administration. 4-Hydroxy-alprazolam was the predominant metabolite in serum samples while alpha-hydroxy-alprazolam was not detected. 3. The mean oral clearance of alprazolam was 1.15 +/- 0.32 ml min-1 kg-1. The time course of alprazolam in milk roughly paralleled the perspective plasma time profile (mean serum residence time = 16.42 +/- 4.69 h; mean milk residence time = 18.93 +/- 7.03 h). The mean terminal half-life in serum was 12.52 +/- 3.53 h. 4. Observed milk/serum concentration ratios were determined in vivo as AUCmilk/AUCserum (mean M/S(obs) = 0.36 +/- 0.11).(ABSTRACT TRUNCATED AT 250 WORDS)