Today a majority of all newborn infants are breast fed and may be exposed to a variety of drugs and environmental contaminants via milk. In order to assess the potential for harm, it is essential to be able to predict the amount of drug presented to the neonate. Even more critical is an understanding of the relationship between dose, steady-state unbound concentration and the pharmacological/toxicological effect in the neonate. The current proposal will expand on these key issues raised in the original submission. The principal working hypothesis states that most xenobiotics are transferred into milk via passive diffusion and their passage can readily be predicted a priori from in vitro experiments. While this model worked well in the rabbit (predicting M/S ratios for 10 drugs), it did not predict the large M/S observed for cimetidine, ranitidine and nitrofurantoin in the rat. An alternative hypothesis would hold that some xenobiotics are transferred into milk via an active transport process which may vary across animal species. To test the predictability of the diffusion model in the rat, a series of infusion experiments will be conducted in the lactating rat using compounds which are likely to conform to the diffusion model (antipyrine, salicylic acid and diazepam) and a series of cations (cimetidine, ranitidine and procainamide) and anions (p-aminohippurate, nitrofurantoin and probenecid) known to be actively transported in other tissues (i.e., renal tubule). The diffusion model will be tested directly in the human population using caffeine and cimetidine. To evaluate the impact of nursing and maternal dosing schedule, the accumulation of phenobarbital and diazepam in rabbit pups and the accumulation of phenobarbital and cimetidine in rat pups will be examined following multiple dose administration at two stages of development (2 and 4 weeks postpartum). To examine the dose (concentration)-response profile in the neonate phenobarbital, a classic cytochrome P-450 enzyme inducer will be administered. These studies will characterize the induction response using in vivo metabolism (antipyrine and caffeine pharmacokinetics), in vitro isozyme activity (testosterone and alkoxyresorufin oxidation; glucuronidation) and protein regulation (mRNA) in adult rats and rat pups. Drug analysis will be carried out by HPLC, while in vitro assessments of M/S ratios will employ equilibrium dialysis/centrifugation techniques. Metabolism and molecular biology experiments will include: cDNA and oligo probes to analyze cytochrome P-450 mRNA, and testosterone and resorufin in vitro enzyme-substrate assays. Successful completion of these studies will contribute to a fundamental understanding of rational drug use in the nursing mother and the consequences for the suckling newborn.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM038836-04A1
Application #
3295552
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1988-09-01
Project End
1996-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Oo, C Y; Paxton, E W; McNamara, P J (2001) Active transport of nitrofurantoin into rat milk. Adv Exp Med Biol 501:547-52
Gerk, P M; Oo, C Y; Paxton, E W et al. (2001) Interactions between cimetidine, nitrofurantoin, and probenecid active transport into rat milk. J Pharmacol Exp Ther 296:175-80
Gerk, P M; Paxton, E W; Bandyopadhyay, A M et al. (2001) Influence of lysine on cimetidine uptake and on excretion of cimetidine by the rat mammary gland. Adv Exp Med Biol 501:553-8
McNamara, P J; Meece, J A; Paxton, E (1996) Active transport of cimetidine and ranitidine into the milk of Sprague Dawley rats. J Pharmacol Exp Ther 277:1615-21
Oo, C Y; Burgio, D E; Kuhn, R C et al. (1995) Pharmacokinetics of caffeine and its demethylated metabolites in lactation: predictions of milk to serum concentration ratios. Pharm Res 12:313-6
Oo, C Y; Kuhn, R J; Desai, N et al. (1995) Active transport of cimetidine into human milk. Clin Pharmacol Ther 58:548-55
Oo, C Y; Kuhn, R J; Desai, N et al. (1995) Pharmacokinetics in lactating women: prediction of alprazolam transfer into milk. Br J Clin Pharmacol 40:231-6
Yoo, S D; Burgio, D E; McNamara, P J (1994) Phenobarbital disposition in adult and neonatal rabbits. Pharm Res 11:1204-6
McNamara, P J; Burgio, D; Yoo, S D (1992) Pharmacokinetics of cimetidine during lactation: species differences in cimetidine transport into rat and rabbit milk. J Pharmacol Exp Ther 261:918-23
McNamara, P J; Burgio, D; Yoo, S D (1992) Pharmacokinetics of caffeine and its demethylated metabolites in lactating adult rabbits and neonatal offspring. Predictions of breast milk to serum concentration ratios. Drug Metab Dispos 20:302-8

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