Excretion of high concentrations of cimetidine and ranitidine into rat milk and their effects on milk composition and mammary gland nucleic acid content.
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 micrograms/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.
National Institute of Environmental Health Sciences, National Toxicology Program, Research Triangle Park, North Carolina 27709.
L A
LA
Dostal
R P
RP
Weaver
B A
BA
Schwetz
D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000818:Animals; D002927:Cimetidine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D005260:Female; D007774:Lactation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000378:metabolism; D008657:Metabolic Clearance Rate; D008892:Milk / Q000378:metabolism*; D011247:Pregnancy; D012313:RNA / Q000378:metabolism*; D011899:Ranitidine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D012313:RNA; D002927:Cimetidine; D011899:Ranitidine; D004247:DNA; D000633:Aminopyrine N-Demethylase