XENOBIOTIC TRANSFER INTO MILK-DIFFUSTIONAL MODEL

今天，大多数新生婴儿都是母乳喂养的，可能会接触到 通过牛奶传播到各种药物和环境污染物。按顺序 要评估潜在的危害，必须能够预测 提供给新生儿的药物的量。更关键的是 对剂量、稳态非束缚关系的认识 浓度和药理/毒理作用 刚出生的。目前的提案将对#年提出的这些关键问题进行扩展 原始意见书。主要的工作假说指出 大多数外来物质是通过被动扩散转移到牛奶中的 从体外可以很容易地预先预测它们的通过。 实验。虽然该模型在兔身上运行良好(预测M/S 10种药物的比率)，它没有预测到观察到的大M/S 西咪替丁、雷尼替丁和呋喃妥因对大鼠的影响。另一种选择 假说认为一些外源物质是通过 一种主动的运输过程，可能会因动物物种而异。至 在大鼠体内测试扩散模型的可预测性，一系列 输液实验将在哺乳期大鼠身上进行，使用 可能符合扩散模型的化合物(安替比林， 水杨酸和安定)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、呋喃妥因 和丙磺舒)已知在其他组织中被主动转运(即， 肾小管)。扩散模型将直接在人体内进行测试 使用咖啡因和西咪替丁的人群。评估……的影响 护理和产妇给药计划，苯巴比妥的蓄积 和安定以及苯巴比妥和苯巴比妥在仔兔体内的蓄积 西咪替丁在多次给药后将在大鼠幼鼠体内进行检测 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的特征 利用体内代谢(安替比林和咖啡因药代动力学)， 体外同工酶活性(睾酮和烷氧基间苯二酚氧化； 成年大鼠和大鼠的糖醛酸化作用)和蛋白质调节(MRNA) 小狗。药物分析将采用高效液相色谱法，而在体外 M/S比例的评估将采用平衡透析/离心法 技巧。新陈代谢和分子生物学实验将包括： 细胞色素P-450mRNA和睾酮的cDNA和寡核苷酸探针分析 和间苯二酚体外酶底物测定法。成功完成 这些研究将有助于从根本上理解理性 哺乳母亲用药情况及其对哺乳的影响 刚出生的。

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.