XENOBIOTIC TRANSFER INTO MILK--DIFFUSIONAL MODEL

今天，超过一半的新生儿是母乳喂养的， 哺乳期的婴儿接触到各种各样的药物， 环境污染物通过母乳。 作为第一种方法， 为了确定异生物质对新生儿的安全性或危害， 必须能够预测药物的量 给新生儿（剂量）。 在人类和兔子中的初步工作 表明药物M/P比值（因此新生儿剂量）可以 从简单的实验室实验预测，使用扩散 模型 然而，更重要的是要了解这些 影响作用部位药物浓度的因素 通过乳汁急性/慢性给药后的新生儿。 这 建议将系统地评估影响这条路线的因素 新生儿药物暴露 建议的扩散模型将是 通过比较体外（蛋白结合） 和脂肪分配）和体内（单次静脉给药）M/P值 各种系列的药物：对乙酰氨基酚（APAP），安替比林（A）， 咖啡因（CA）、西咪替丁（CI）、依曲亭（E）、六氯苯 (HCB)和水杨酸（SA）。 多次口服给药研究（APAP， SA）将评价给药途径和速率对 新生儿暴露。 模型的静脉给药、清除研究 化合物（APAP，A，CA，CI）将在新生儿中建立 改变的消除途径（代谢和肾脏）及其 对生物累积的影响。 APAP的生物利用度评估， A、CA和CI将有助于区分可用剂量和 吸收剂量;确定新生儿的吸收问题 兔子 其他研究（气候变化、六氯代苯）将评估 护理和母体给药方案对新生儿蓄积的影响。 将通过以下方法建立体外血浆和乳汁蛋白结合率： 平衡透析，以及全脂奶到脱脂奶的分配， 离心法 这些化合物的体内浓度-时间过程 将通过HPLC和GLC跟踪血浆和乳汁中的外源性物质 方法. 成功完成这些研究将提供 护理合理用药的基本依据 母亲，特别是： 在人类研究不道德的情况下，建立一个 药物产品选择的科学依据， 药物相互作用和疾病状态对新生儿暴露的影响， 为将动物实验结果外推至人类提供了基础 预测由于大量的 新生儿剂量或不成熟的消除能力。

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.