Kinetics of Renal Disposition and Action of Bioactive Peptides

本研究的目的是定量研究肾脏清除对全身清除的贡献，并对多肽的药理和毒性作用进行动力学研究。用NONMEN程序分析万古霉素在日本患者的群体药动学分布。在成人中，当内生肌酐清除量(CLcr)小于85ml/min时，万古霉素清除量与内生肌酐清除量(CLcr)呈线性相关。在儿科患者中，万古霉素清除量在1岁以下随年龄增加而增加，在1岁以上随年龄增加而减少。根据这些结果，提出了最佳给药间隔与达到稳态峰值和低谷浓度所需的CLcr的关系图，分别为50ug/ml和7.5ug/ml。对谷浓度与肾脏异常发生率关系的非参数二元回归分析表明，谷浓度与肾脏异常发生率之间的关系随氨基糖苷剂量的增加而增加，只要谷浓度控制在10微克/毫升以下，肾脏异常发生率就有可能降至15%以下。本文还研究了环孢素A的药代动力学。尼卡地平与硝酸甘油合用可降低环孢素清除量，但硝酸甘油不影响环孢素清除量。

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.