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

确定抗菌剂组织分布随年龄变化的因素的定量分析

• 批准号: 61571094
• 负责人: TSUJI Akira
• 金额: $ 1.22万
• 依托单位: KANAZAWA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1986
• 资助国家: 日本
• 起止时间: 1986 至 1987
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-61571094/
• 关键词: Tissue distribution; Peptide transport system; Organic anion transport system; Serum protein binding; Antimicrobial agent; <beta>-lactam antibiotics; cefazolin; セファゾリン; ジプペチド輸送系; 抗菌性抗生物質

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.

本研究的目的是建立定量预测药物组织分布变化的药代动力学方法，并与组织的生理和解剖功能变化相联系<beta>。小肠、肝脏和肾脏中的膜转运机制; 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中年龄相关变化的因素。获得了以下结果：1. <beta>- 内酰胺类抗生素可以被存在于肠刷状缘膜中的二肽载体系统识别并通过其转运; 2.然而，在非消除器官中，这些抗生素不能转运细胞膜，不能定位在间质液空间内，也不能与该液体中的白蛋白结合。基于这种组织分布机制，建立了生理药代动力学模型，定量预测β-内酰胺类抗生素之一的头孢唑林<beta>在1、7、50和100周龄大鼠体内的组织分布变化; 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细菌感染儿科患者中的稳态分布容积。间接胆红素与白蛋白摩尔比的变化是导致血浆中头孢唑林游离分数个体差异的主要原因，这成为决定该抗生素在新生儿体内组织分布的主要因素。

项目成果

Tsuji,A.,et al.(辻彰他): J.Pharm.Pharmacol.36. 565-567 (1987)

Tsuji，A. 等人：J.Pharm.Pharmacol.36（1987 年）。

Tamai, I., et al.: "Stereospecific absorption and degradation of cephalexin" J. Pharm. Pharmacol.37. (1988)

Tamai, I., et al.：“头孢氨苄的立体特异性吸收和降解”J. Pharm。

Tsuji,A.,et al.(辻彰他): J.Pharmacol.Exp.Ther.241. 594-601 (1987)

Tsuji，A. 等人：J.Pharmacol.Exp.Ther.241（1987 年）。

Terasaki, T., et al.: "Age-related change of cefazolin binding to rat serum proteins and its relationship to the molar ratio of free fatty acid to serum albumin" J. Pharmacobio-Dyn.9. 81-87 (1986)

Terasaki, T. 等人：“头孢唑林与大鼠血清蛋白结合的年龄相关变化及其与游离脂肪酸与血清白蛋白摩尔比的关系”J. Pharmacobio-Dyn.9。

Tsuji, A.: Intestinal absorption of beta-lactam antibiotics. In "Frontiers of Antibiotic Research ", ed. by Umezawa, H., Academic press Japan, Japan, pp255-268 (1987)

Tsuji, A.：β-内酰胺抗生素的肠道吸收。