Short communication

Investigation of the mechanisms of the extensive excretion of cimetidine into rat milk

Recent scientific and regulatory interest in lacteal excretion of drugs has prompted this review of bioanalytical sample preparation techniques for milk. The composition and properties of milk are reviewed, with emphasis on how the sample preparation is affected. The most important principals of mammary gland pharmacology, including protein binding, ion trapping and liquid solubility, are described. Because adequate milk volume is difficult to obtain from some smaller rodent species, special arrangements for sample collection, control preparation and assay standardization often need to be made. Several commonly-used sample preparation approaches for drugs in milk, including direct injection, dialysis and ultrafiltration, protein precipitation, liquid-liquid extraction, solid-phase extraction and immunoaffinity extraction, have been reported with varying degrees of success. The advantages and disadvantages of each of these approaches is discussed.

In recent years, concern about possible female reproductive and developmental toxicity due to environmental contaminants, such as PCBs, has been growing. Because this area of toxicology had not been emphasized prior to this time, there are many gaps in current knowledge about female developmental and reproductive toxicology and only a limited number of validated tests to assay effects of toxicants on various parts of the reproductive and developmental cycle. This article reviews the current state of knowledge on this topic and also explores a variety of techniques for assessing female reproductive and developmental toxicity. These include an assay of the state of intercellular communication among the embryo, fetus and placenta; protocols for assessing toxicity in early pregnancy; and techniques for evaluating the role of glutathione in protecting the conceptus from xenobiotics.

The excretion of cimetidine and ranitidine into rat milk following single or multiple oral doses and the subsequent effects on their suckling pups and on milk composition and milk synthesis were investigated. Following a single dose of [³H]cimetidine, peak milk cimetidine concentrations were maintained from 1 until 4 hr, while plasma concentrations peaked at 10% of the milk level at 30 min and then declined. Multiple doses of cimetidine (18 or 180 mg/kg/day) on Days 13–16 of lactation led to milk cimetidine concentrations of 17 and 113 μg/ml. The milk/plasma ratios far exceeded the theoretical milk/plasma ratio of 2.0. Ranitidine concentrations in rat milk following ranitidine treatment (4.5 or 45 mg/kg/day) were also greater (6.8–15 times) than in plasma, but only slightly greater than the predicted ratio of 5.0. There were no changes in liver weight or in hepatic aminopyrine N-demethylase activity in the cimetidine- or ranitidine-treated dams or their pups. Cimetidine treatment had no effect on milk lipid, solid, or protein content, but at 180 mg/kg/day, caused a significant increase in milk lactose. The RNA/DNA ratio in the mammary gland was significantly increased by cimetidine, suggesting increased milk synthesis. Ranitidine had no effect on milk composition or on mammary gland RNA, DNA, or RNA/DNA. Therefore, high concentrations of cimetidine and ranitidine were excreted into rat milk, but no deleterious effects on the suckling pups, or the composition of the milk, or on the milk synthetic activity were observed.