XENOBIOTIC TRANSFER INTO MILK--DIFFUSIONAL MODEL

今天，超过一半的新生儿是母乳喂养的， 哺乳婴儿暴露在各种各样的药物和 通过母乳污染环境。作为第一种方法 以确定外源生物对新生儿的安全性或危害， 能够预测所呈现的药物的量是至关重要的 对新生儿(剂量)。在人类和兔子身上的初步工作 表明药物的M/P比率(因此新生儿剂量)可以是 根据简单的实验室实验使用扩散进行预测 模特。然而，更关键的是理解这些 影响药物作用部位药物浓度的因素 通过牛奶急性/慢性给药后的新生儿。这 建议书将系统地评估制约这条路线的因素 新生儿药物暴露的风险。建议的扩散模型将是 通过比较体外(蛋白质结合)在兔身上的验证 和脂肪分配)和体内(单次静脉注射)M/P值 不同系列的药物：对乙酰氨基酚(APAP)、安替比林(A)、 咖啡因(CA)、西咪替丁(CI)、茶多酚(E)、六氯苯 (HCB)和水杨酸(SA)。多剂量口服研究(APAP， SA)将评估给药路线和给药速度对 新生儿接触。模型静脉给药剂量、清除量的研究 新生儿体内的化合物(APAP、A、CA、CI)将建立 代谢和肾脏代谢途径的改变及其机制 对生物积累的影响。APAP的生物利用度评价， A、CA和CI将有助于区分可用剂量和 吸收的剂量；确定新生儿的吸收问题 兔子。其他研究(CA、HCB)将评估 新生儿蓄积的护理及母体给药方案。 在体外，血浆和乳蛋白结合将通过以下方式建立 平衡透析法和全脂脱脂牛奶分割法 离心法。这些药物在体内的浓度-时间过程 血浆和牛奶中的外源物质将用高效液相和气相色谱进行跟踪 方法：研究方法。成功完成这些研究将提供 合理用药在护理中的基本依据 母亲，具体地说：估计#年人类新生儿剂量 在人体研究不道德的情况下，建立一个 为药品选择提供科学依据，预测影响 药物相互作用和疾病状态对新生儿暴露的影响， 为人类推断动物结果提供了基础 会对新生儿造成风险的预测剂 新生儿剂量或未成熟排泄能力。

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.