XENOBIOTIC TRANSFER INTO MILK-DIFFUSTIONAL MODEL

今天，大多数新生儿都是母乳喂养的， 通过牛奶接触到各种药物和环境污染物。 为了 为了评估潜在危害，必须能够预测 给新生儿的药量。 更重要的是， 了解剂量、稳态未结合 浓度和药理学/毒理学效应 新生儿 目前的建议将扩大对这些关键问题提出的， 原始提交。 主要工作假设指出， 大多数外源性物质通过被动扩散转移到乳汁中， 它们的传代可以很容易地从体外预先预测 实验 虽然这个模型在兔子身上工作得很好（预测M/S 10种药物的比值），但不能预测 西咪替丁、雷尼替丁和呋喃妥因。 一个替代 假设认为，一些外源性物质通过 这是一个主动的运输过程，可能会因动物物种而异。 到 在大鼠中测试扩散模型的可预测性， 输注实验将在哺乳大鼠中进行， 可能符合扩散模型的化合物（安替比林， 水杨酸和地西泮）和一系列阳离子（西咪替丁， 雷尼替丁和普鲁卡因胺）和阴离子（对氨基马尿酸盐、呋喃妥因 和丙磺舒）已知在其它组织中被主动转运（即， 肾小管）。 扩散模型将直接在人体中进行测试 使用咖啡因和西咪替丁的人群。 的影响进行评估 护理和母体给药方案，苯巴比妥蓄积 和地西泮，以及苯巴比妥的蓄积， 将在多次给药后检查大鼠幼仔中的西咪替丁 在两个发育阶段（产后2周和4周）给药。 检查新生儿的剂量（浓度）-反应曲线 苯巴比妥，一种经典的细胞色素P-450酶诱导剂， 管理。这些研究将描述诱导反应 使用体内代谢（安替比林和咖啡因药代动力学）， 体外同工酶活性（睾酮和烷氧基试卤灵氧化; 葡萄糖醛酸化）和蛋白质调节（mRNA）在成年大鼠和大鼠 小狗 药物分析将通过HPLC进行，而在体外 M/S比的评估将采用平衡透析/离心 技术. 代谢和分子生物学实验将包括： 用于分析细胞色素P-450 mRNA和睾酮的cDNA和寡核苷酸探针 和试卤灵体外酶-底物测定。 成功完成 这些研究将有助于从根本上理解理性 哺乳期母亲的药物使用及其对哺乳期婴儿的影响 新生儿

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.