Amphotericin B-induced nephrotoxicity: characterization of blood and urinary biochemistry and renal morphology in mice.
This study was conducted to characterize blood and urinary biochemistry, and renal morphology, after single or 1-week repeated dosing of mice with the polyene macrolide antibiotic, amphotericin B (AMB). AMB was intravenously administered to mice at 2 or 4 mg/kg for the single-dose experiment or once daily at 1 or 2 mg/kg for 1 week for the repeated-dose experiment. The most prominent histopathological findings included necrosis of the tubular epithelial cells in the thick ascending limb of Henle's loop in the renal outer medulla at a single dose of 2 or 4 mg/kg, and the severity of the lesion was dose-dependent. Blood chemistry and urinalysis revealed several changes suggestive of renal dysfunction such as reduction of plasma filtration ability (increases in plasma creatinine and blood urea nitrogen, a decrease in creatinine clearance) and polyuria accompanied with dehydration (decrease in renal water reabsorption, increases in plasma total protein and albumin) at a dose of 4 mg/kg in the single-dose experiment. Among the parameters analyzed, urinary lactate dehydrogenase was the most sensitive and reliable parameter for the prediction of AMB-induced nephrotoxicity in mice. These data provided comprehensive information on the nephrotoxicity of AMB and indicate useful markers for the sensitive detection of AMB-induced renal injury in mice.
Tonomura
Y
Y
Drug Safety Evaluation, Developmental Research Laboratories, Toyonaka, Osaka 561-0825, Japan.
Yamamoto
E
E
Kondo
C
C
Itoh
A
A
Tsuchiya
N
N
Uehara
T
T
Baba
T
T
D000666:Amphotericin B / Q000633:toxicity*; D000818:Animals; D000935:Antifungal Agents / Q000633:toxicity*; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000097:blood / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009929:Organ Size / Q000187:drug effects; D012372:ROC Curve; D016482:Urinalysis
D000935:Antifungal Agents; D000666:Amphotericin B; D003404:Creatinine