Quantitative analysis of factors determining age-related change in tissue distribution of animicrobial agents

本研究的目的是建立药代动力学方法，定量预测药物在组织中的分布变化与组织生理解剖功能的变化之间的关系。我们研究过，关于< β >-内酰胺：抗生素：1。小肠、肝、肾的膜转运机制；2. 血清蛋白结合机制；3. 定量分析决定动物和人类组织分布年龄相关变化的因素。得到了以下结果：1。< β - >-内酰胺类抗生素可被存在于肠刷缘膜的二肽载体系统识别并通过其运输；2. 然而，在非消除器官中，这些抗生素不能运输细胞膜，不能在组织液空间内定位，也不能与组织液中的白蛋白结合。基于这一组织分布机制，建立了< β - >-内酰胺类抗生素之一头孢唑林的生理药代动力学模型，定量预测头孢唑林在1、7、50、100周龄大鼠组织分布的变化；3. 我们的理论在实验动物中得到验证，并应用于预测头孢唑林在儿童细菌感染患者的稳态分布体积。间接胆红素与白蛋白摩尔比的变化是头孢唑林血浆中未结合部分的个体差异的主要原因，这是决定头孢唑林在新生儿中组织分布的主要因素。

The purpose of this study is to establish the pharmacokinetic method to predict quantitatively the change in the tissue distribution of drugs in relation to the change in the physiological and anatomical functions of tissues.We have studied, about <beta>-lactam: antibiotics: 1. membrane transport mechanism in the small intestine, liver and kidney; 2. mechanism of the serum protein binding; 3. quantitative analysis for the factors determining the age-related change in the tissue distribution in animals and humans. The following results were obtained: 1. <beta>-lactam antibiotics can be recognized by and transported through the dipeptide carrier system(s) existing in the intestinal brush-border membrane; 2. In noneliminating organs, however, these antibiotics cannot transport cell membranes and localize within the interstitial fluid space and bind with albumin in this fluid. Based on this tissue distribution mechanism, the physiological pharmacokinetic model was developed to predict quantitatively the change in the tissue distribution of cefazolin, one of <beta>-lactam antibiotics, in 1-, 7-, 50-and 100-weeks-old rats; 3. Our theory verified in laboratory animals was applied to predict the volume of distribution at steady state for cefazolin in pediatric patients with bacterial infections. The change of indirect bilirubin to albumin molar ratio is predominantly responsible for the individual variation in the fraction unbound of cefazolin in plasma, which becomes the major factor determining the tissue distribution of this antibiotic in newborn infants.