Evaluation of imipenem toxicity in cynomolgus macaques including assessment of biomarkers of renal damage
作者单位：Centre for Drug Safety Evaluation and ResearchShanghai Institute of Materia Medica
会议名称：《2013年（第三届）中国药物毒理学年会暨药物非临床安全性评价研究论坛》
会议日期：2013年
学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学]
关 键 词：imipenem toxicity biomarkers renal damage
摘 要：OBJECTIVE To assess the nephrotoxicity of imipenem and to correlate the pathogenesis of lesions in the kidney with changes in urinary biomarkers of kidney *** Study #1,11 monkeys(2 -3/sex/group) were given vehicle or imipenem(180 mg·kg,iv infusion once daily for 7 d) and urine was collected on days xxxxx for biomarker *** Study #2,24 monkeys(3/sex/group) were given of vehicle or imipenem(45,90 or 180 mg·kg,iv infusion once daily for 7 d).The following endpoints were assessed in both studies:clinical observations,body weight, food consumption,haematology,coagulation,blood chemistry,urine analysis,imipenem concentration/toxicokinetics (TK) and gross and microscopic *** Study #1:Imipenem causes minor body weight loss,increased urea and creatinine,and decreased phosphate in *** total protein and bilirubin were observed in the urine. These effects were progressive and most pronounced at days 7 and *** and relative kidney weights were increased in both *** histopathological findings were present in kidneys of the dosed monkeys,consisting of minimal to moderate tubular necrosis/degeneration/*** biomarkers(α-1 andβ-2 microglobulin,clusterin, Tamm-Horsfall protein and vascular endothelial growth factor) increased progressively and significantly from day 2 onward and preceded notable changes in urinalysis or plasma chemistry on day 7 or 8,*** #2:There were similar findings to Study #1 in the 180 mg·kg imipenem treatment *** total bilirubin and decreased of phosphate in plasma and an increase of urinary urobilinogen/ketones were observed in a dose related *** to imipenem [C and AUC(0-3h))) increased in proportion from 45 -90 mg-kg but more than in proportion from 90-180 mg·kg. CONCLUSION The no observed adverse effect level(NOAEL) for the imipenem induced kidney injury was identified as 90 mg·*** increases of five urinary biomarkers of kidney toxicit