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 character- ize 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 f 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 (t,,) in milk (3.3 +- 0.7 hours) displayed a delay compared with serum L= (1.7 + 0.6 hours). Oral clearance for 1200 mg ci- me&line 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 suck- linginfant. (CLINPHARMA COL THER 1995;58:548-55.) Cheah Y. 00, Robert J. Kuhn, PharmD, Nirmala Desai, MD, and Patrick J. McNamara, PhD Lexingpon, Ky, The percentage of women who initially breastfeed increased from 28% in the 1960s to 54% in the 1980s and appeared to level off or decline slightly to 52% in the 1990s in the United States.’ The prevalence of breastfeeding is consistent with findings purporting the benefits to suckling infants and mothers.233 The composition of human milk is very complex. In addi- tion to nutrients such as proteins, fats, sugars, miner- als, and vitamins, there are antibodies, hormones, and growth factors thought to be integral to the infant’s growth.1,3-5 Most xenobiotics are presumed to be transferred by passive diffusion into breast milk, From the Division of Pharmacology and Experimental Therapeutics and Division of Pharmacy Practice and Science, College of Phat- macy, and the Department of Pediatrics, College of Medicine, University of Kentucky. Received for publication March 17, 1995; accepted June 26, 1995. Supported in part by General Clinical Research Center grant (RR02602) and grant (GM 38836) from the National Institutes of Health, Bethesda, Md. Reprint requests: Patrick J. McNamara, PhD, Pharmacology and Ex- perimental Therapeutics, University of Kentucky, College of Pharmacy, Rose St., Lexington, KY 40536-0082. Copyright 0 1995 by Mosby-Year Book, Inc. 0009-9236/95/$5.00 + 0 13/l/67423 548 where the milk concentrations can be predicted on the basis of their physicochemical properties.6’7 However, passive diffusion may be inadequate to ensure a rich yet precise supply of essential maternal substrates to the suckling infant. Mammary epithelial transport sys- tems may be needed to concentrate and regulate the influx of endogenous substrates from maternal blood into milk. Certain exogenous compounds may accu- mulate into milk through these same mammary trans- port systems. Cimetidine is an H,-receptor antagonist with wide clinical application, including its use in pediatric pa- tients and nursing mothers. It is a weak base, with a pK, of 6.8,’ and is partially charged at physiologic pH. Cimetidine has become a prototypic compound for the study of organic cation transfer because of its high renal active secretion.9-‘2 In addition, cimetidine has been shown to accumulate into hepatocytes13”4 and the choroid plexus. 15,16 Cimetidine transfer into rabbit milk appears to be governed by diffusion, whereas cimetidine excretion into rat milk seems to involve an active transport mechanism.*7 The extent and mechanism of cimetidine transfer into human milk is largely unknown, except for one case report that