Mechanisms and pharmacokinetic/pharmacodynamic profiles underlying the low nephrotoxicity and ototoxicity of etimicin  

作　　者：Lan Yao Jing-wei Zhang Bin Chen Ming-min Cai Dong Feng Qi-zhi Wang Xin-yu Wang Jian-guo Sun Yi-wen Zheng Guang-ji Wang Fang Zhou 

机构地区：[1]Key Laboratory of Drug Metabolism and Pharmacokinetics,State Key Laboratory of Natural Medicines,China Pharmaceutical University,Nanjing 210009,China [2]Department of Pharmacology and Toxicology,School of Biomedical Sciences and Brain Health Research Centre,University of Otago,Dunedin 9016,New Zealand [3]Brain Research New Zealand,Dunedin 9016,New Zealand [4]Eisdell Moore Centre for Hearing and Balance Research,University of Auckland,Auckland 1142,New Zealand

出　　处：《Acta Pharmacologica Sinica》2020年第6期866-878,共13页中国药理学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(81573496,81773989,81530098,and 81573494);the China"Creation of New Drugs"Key Technology Projects(2015ZX09501001,2017ZX09304021);the National Science and Technology Major Project of China(2019ZX09721001-006-005);the International Science and Technology Cooperation Program of China(2017YFE0109600);the Foundation for Innovative Research Groups of the National Natural Science Foundation of China(No.81421005);the Natural Science Foundation of Jiangsu Province(No.BK20160076);the six talent peaks project in Jiangsu Province(YY-060);and the"Double First-Class"University project(CPU2018GF01).

摘　　要：Etimicin(ETM),a fourth-generation aminoglycosides(AGs),is now widely clinically used in China due to its high efficacy and low toxicity.However,the mechanisms underlying its low nephrotoxicity and ototoxicity remain unclear.In the present study we compared the antibacterial and toxicity profiles of etimicin,gentamicin(GM,a second-generation AG),and amikacin(AMK,a third-generation AG),and investigated their pharmacokinetic properties in the toxicity target organs(kidney and inner ear)and subcellular compartments.We first demonstrated that ETM exhibited superior antibacterial activities against clinical isolates to GM and AMK,and it exerted minimal nephrotoxicity and ototoxicity in rats following multi-dose administration.Then,we conducted pharmacokinetic studies in rats,showed that the three AGs accumulated in the kidney and inner ear with ETM being distributed to a lesser degree in the two toxicity target organs as compared with GM and AMK high-dose groups.Furthermore,we conducted in vitro experiments in NRK-52E rat renal tubular epithelial cells and HEI-OC1 cochlear hair cells,and revealed that all the three AGs were distributed predominantly in the mitochondria with ETM showing minimal accumulation;they not only directly inhibited the activity of mitochondrial complexesⅣandⅤbut also inhibited mitochondrial function and its related PGC-1α-NRF1-TFAM pathway;ETM caused minimal damage to the mitochondrial complex and mitochondrial biogenesis.Our results demonstrate that the minimal otonephrotoxicity of ETM results from its lesser accumulation in mitochondria of target cells and subsequently lesser inhibition of mitochondrial function.These results provide a new strategy for discovering novel AGs with high efficacy and low toxicity.

关 键 词：AMINOGLYCOSIDE ETIMICIN gentamicin AMIKACIN NEPHROTOXICITY OTOTOXICITY pharmacokinetics mitochondria 

分 类 号：R96[医药卫生—药理学]