XENOBIOTIC TRANSFER INTO MILK--DIFFUSIONAL MODEL

异生素转移到牛奶中——扩散模型

• 批准号: 3295550
• 负责人: Patrick J McNamara
• 金额: $ 11.3万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-09-01 至 1991-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3295550
• 关键词: acetaminophen; antipyrine; binding proteins; biological models; breast feeding; caffeine; chlorobenzenes; cimetidine; drug adverse effect; drug delivery systems; environmental contamination; food chain; laboratory rabbit; milk; nutrient bioavailability; placental transfer; salicylate; toxin metabolism

Today greater than half of all newborn infants are breastfed and nursing infants are being exposed to a wide variety of drugs and environmental contaminants via breast milk. As a first approach to determining the safety or hazard of xenobiotics to the neonate, it is essential to be able to predict the amount of drug presented to the neonate (dose). Preliminary work in humans and rabbits suggests that drug M/P ratios (hence neonatal dose) can be predicated from simple laboratory experiments using a diffusion model. However, even more critical is an understanding of those factors affecting drug concentration at the site of action in the neonate following acute/chronic administration via milk. This proposal will systematically evaluate factors governing this route of neonatal drug exposure. The proposed diffusion model will be validated in the rabbit by comparing the in vitro (protein binding and fat partitioning) and in vivo (single iv dose) M/P values for a varied series of agents: acetaminophen (APAP), antipyrine (A), caffeine (CA), cimetidine (CI), etretin (E), hexachlorobenzene (HCB) and salicylic acid (SA). Multiple oral dose studies (APAP, SA) will evaluate impact of route and rate of administration on neonatal exposure. Intravenous dose, clearance studies of model compounds (APAP, A, CA, CI) in the neonate will establish altered elimination pathways (metabolic and renal) and their impact on bioaccumulation. Bioavailability assessment of APAP, A, CA, and CI will help distinguish between dose available and dose absorbed; identify absorption problems in the neonatal rabbit. Additional studies (CA, HCB) will evaluate the impact of nursing and maternal dosing schedule on neonatal accumulation. In vitro plasma and milk protein binding will be established by equilibrium dialysis, and whole to skim milk partitioning by centrifugation. The in vivo concentration-time course of these xenobiotics in plasma and milk will be followed by HPLC and GLC methods. Successful completion of these studies will provide the fundamental foundation for rationale drug use in the nursing mother, specifically: estimating human neonatal doses in situations where human studies are unethical, establishing a scientific basis for drug product selection, predicting the impact of drug interactions and disease states on neonatal exposure, providing a basis for extrapolating animal results to man predicting agents posing a risk to the neonate due to substantial neonatal dose or immature elimination capacity.

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