Comparision Of The Nephrotoxicity Of Aminoglycoside Antibiotics And In Vitro Toxicogenomics Study

The kidney is a common target organ of chemical-induced toxicity. Many drugs can contribute to renal injury. In recent years, animal experiments are still the basic method of nephrotoxicity evaluation. In vitro alternative model to assess toxicity and screen leading candidate compounds at early stage of drug development is one of the targets in discovery toxicology. The rapid development of toxicogenomics may also solve many problems happened in traditional animal toxicity experiments and to consummate further the system of drug safety evaluation and research. It is known that clinical use of aminoglycoside antibiotics (e.g. gentamicin) is mainly restricted by its nephrotoxicity but the toxic mechanism remains unclear. Vertilmicin (VTM) is a kind of novel aminoglycoside antibiotic, which was found during the synthesis of netilmicin and proved to possess better anti-bacterial activity than netilmicin. As a new drug, vertilmicin is under development in China.In the present study, in vivo nephrotoxicity of vertilmicin, netilmicin and gentamicin were compared using Sprague-Dawley rats. Cultured human renal tubular epithelial cell line(HK-2) was used as an in vitro model for toxicity evaluation. Additionally, a toxicogenomics study was conducted to investigate the toxic mechanism of aminoglycoside antibiotics usinggene microarray technique..Firstly, comparative nephrotoxicity of vertilmicin, netilmicin and gentalicin was examined in Sprague-Dawley rats. Animals were treated by im injection once daily at doses of 25, 50, 100 mg.kg^-1.d^-1 for 15 days. Control rats were injected with saline. The following parameters were examined: clinical signs, clinical chemistry, urinalysis,...