Active transport of cimetidine into human milk*

Abstract

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.

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…The ability of the mammary gland to concentrate pharmaceuticals such as nitrofurantoin and cimetidine in human breast milk has been recognized (Oo et al, 1995;Gerk et al, 2001). More recently, it was hypothesized that drug transporters may be important in the active transport of chemicals into breast milk.…”

Pharmacokinetics of toxic chemicals in breast milk: use of PBPK models to predict infant exposure.

“…Ionic compounds are not expected to partition into milk in this manner. Some weak bases can preferentially enter the milk as a result of the pH gradient that exists between the blood (pH = 7.4) and milk (pH = 8), whereas other ionic compounds are transported into the milk via active uptake mechanisms (22,23).…”

Stereoselective Interaction of Pantoprazole with ABCG2. II. In Vitro Flux Analysis

“…ABCG2 is expressed on the apical surface of lactating mammary epithelial cells and facilitates the accumulation of substrate drugs in milk, including nitrofurantoin, cimetidine, topotecan, acyclovir, dietary carcinogens, ranitidine, and ciprofloxicin (Oo et al, 1995(Oo et al, , 2001McNamara et al, 1996;Gerk et al, 2001;Jonker et al, 2005;Merino et al, 2005Merino et al, , 2006van Herwaarden et al, 2007;Vlaming et al, 2009). Although diffusion plays a major role in drug appearance in milk, ABCG2 clearly contributes to the accumulation of its substrates in milk.…”