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Kinetics of Renal Disposition and Action of Bioactive Peptides

生物活性肽的肾脏处置动力学和作用

基本信息

批准号：
09672275
负责人：
YASUHARA Masato
金额：
$ 1.98万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672275/
关键词：
peptide drugs vancomycin cyclosporin A population analysis pharmacokinetics renal excretion 腎機能障害

项目摘要

The purpose of the present study is to investigate the contribution of renal clearance on the whole body clearance quantitatively and to clarffy the kinetics of pharmacologic and toxic actions of peptide.We have investigated the renal excretion of vancomycin, a glycopeptide antibiotics. The population pharmacokinetic profile of vancomycin in Japanese patients was analyzed by using the NONMEN program. In adults, vancomycin clearance was linearly correlated with creatinine clearance(CLcr), when CLcr was less than 85 ml/min. In pediatric patients, vancouiycin clearance increased with age up to 1. year of age, and decreased with age over 1 year old. Based on these results, a nomogram that gives the relationship of the optimum dosing interval and the CLcr needed to achieve the steady state peak and trough concentrations of 50 ug/ml and 7.5 ug/ml, respectively, was proposed. Nonparametric binary regression analysis of the relationship between trough concentration and the rate of incidence of the abnormality in the kidney showed that the rate increased with the coadministration of aminoglycosid It is possible to reduce the rate to less than 15 % as long as the trough concentration is kept below 10 ug/mi.The pharmacokinetics of cyclosporin A, a peptidic immunodipressant, was also investigated in rats. It was shown that cyclosporin clearance was reduced by the coadministration of nicardipine, but not affected by nitroglycerin.

本研究旨在定量探讨肾脏清除率对全身清除率的贡献，并阐明肽的药理学和毒性作用动力学。我们研究了万古霉素（一种糖肽类抗生素）的肾脏排泄。使用NONMEN程序分析万古霉素在日本患者中的人群药代动力学特征。在成人中，当CLcr小于85 ml/min时，万古霉素清除率与肌酐清除率（CLcr）呈线性相关。在儿科患者中，温哥华霉素清除率随着年龄的增长而增加，直至1岁。1岁以上随年龄增长而下降。基于这些结果，提出了最佳给药间隔与达到稳态峰谷浓度（分别为50 ug/ml和7.5 ug/ml）所需的CLcr之间的关系图。对谷浓度与肾异常发生率的关系进行非参数二元回归分析，结果表明，与氨基糖苷共给药时，肾异常发生率增加，只要谷浓度保持在10 ug/mi以下，就有可能将肾异常发生率降低到15%以下。研究了肽免疫抑制剂环孢素A在大鼠体内的药代动力学。结果表明，联合使用尼卡地平可降低环孢素的清除率，但不受硝化甘油的影响。