西司他丁对大鼠体内万古霉素肾脏处理的影响。

Effect of cilastatin on renal handling of vancomycin in rats.

作者信息

Kusama M, Yamamoto K, Yamada H, Kotaki H, Sato H, Iga T

机构信息

Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

出版信息

J Pharm Sci. 1998 Sep;87(9):1173-6. doi: 10.1021/js9801135.

DOI:10.1021/js9801135

PMID:9724573

Abstract

To provide insights into the possibility of reducing the nephrotoxicity of vancomycin (VCM) by cilastatin, the effect of cilastatin on the renal handling of VCM, as well as on glomerular filtration rate (GFR) and plasma protein binding of VCM, were studied using rats. After a bolus intravenous (iv) dose of VCM (100 mg/kg), concomitant cilastatin administration (100 mg/kg, iv) resulted in a significant increase in the total VCM clearance and significant decrease in the kidney uptake clearance of VCM, defined as kidney VCM concentration vs AUC ratio. Moreover, after a 3-h continuous iv infusion of VCM (18 or 90 mg/h/kg), significant decrease in the kidney uptake clearance of VCM was observed with concomitant cilastatin iv infusion (300 mg/h/kg). On the other hand, GFR and VCM plasma protein binding did not show any significant change with cilastatin. From the observation that cilastatin decreased the kidney uptake clearance of VCM and enhanced its urinary excretion, it was suggested that cilastatin inhibited the reabsorption of VCM in the renal proximal tubular cells. Thus, it may be possible that cilastatin alleviates the nephrotoxicity of VCM due to reduced accumulation and accelerated renal excretion of VCM.

摘要

为深入了解西司他丁降低万古霉素（VCM）肾毒性的可能性，本研究使用大鼠探讨了西司他丁对VCM肾脏处理过程的影响，以及对VCM肾小球滤过率（GFR）和血浆蛋白结合的影响。静脉推注VCM（100mg/kg）后，同时静脉注射西司他丁（100mg/kg）可使VCM的总清除率显著增加，肾脏摄取清除率显著降低，肾脏摄取清除率定义为肾脏VCM浓度与AUC之比。此外，在连续静脉输注VCM（18或90mg/h/kg）3小时后，同时静脉输注西司他丁（300mg/h/kg）可观察到VCM的肾脏摄取清除率显著降低。另一方面，GFR和VCM血浆蛋白结合率在使用西司他丁后未显示任何显著变化。鉴于西司他丁降低了VCM的肾脏摄取清除率并增强了其尿排泄，提示西司他丁抑制了VCM在近端肾小管细胞中的重吸收。因此，西司他丁可能由于减少了VCM的蓄积并加速了其肾脏排泄而减轻了VCM的肾毒性。