Establishment of a drug-induced rhabdomyolysis mouse model by co-administration of ciprofloxacin and atorvastatin. (July 2018)

• Record Type: Journal Article
• Authors: Matsubara, Akiko; Oda, Shingo; Akai, Sho; Tsuneyama, Koichi; Yokoi, Tsuyoshi
• Is Part Of: Toxicology letters. Volume 291(2018)
• Page Start: 184
• Page End: 193
• Publication Date: 2018-07
• Subjects: ALT alanine aminotransferase -- AST aspartate aminotransferase -- ath Arabidopsis thaliana -- ATV atorvastatin -- BSO l-buthionine-(S, R)-sulfoximine -- BUN blood urea nitrogen -- Cd cluster of differentiation -- CPFX ciprofloxacin -- CPK creatinine phosphokinase -- CRE creatinine -- Gapdh glyceraldehyde-3-phosphate dehydrogenase -- GSH glutathione -- H&E hematoxylin & eosin -- HMG hydroxymethylglutary -- Ho heme oxygenase -- Lcn lipocalin -- Mb myoglobin -- miRNA microRNA -- Ngal neutrophil gelatinase-associated lipocalin -- PAS periodic acid-schiff -- PTAH phosphotungstic acid haematoxylin -- RT reverse transcription -- SMV simvastatin -- Tnf tumor necrosis factor -- Xirp xin actin-binding repeat containing; Drug-induced rhabdomyolysis -- New quinolone antibacterial drug -- Acute kidney injury -- Drug-drug interactions; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2018.04.016
• Languages: English
• ISSNs: 0378-4274

Abstract

Highlights: A rhabdomyolysis mouse model was established by co-administration of ciprofloxacin and atorvastatin. Drugs were orally administered for 4 days to the glutathione-depleted normal mouse. An increase of plasma creatinine phosphokinase (CPK) value and degeneration in the skeletal muscle were observed. Increased area under the curve (AUC) of ciprofloxacin was demonstrated in the co-administered group. Acute kidney injury was induced by myoglobin that leaked from skeletal muscle. Abstract: Rhabdomyolysis is one of the serious side effects of ciprofloxacin (CPFX), a widely used antibacterial drug; and occasionally, acute kidney injury (AKI) occurs. Often, rhabdomyolysis has occurred in patients taking CPFX co-administered with statins. The purpose of this study is to establish a mouse model of drug-induced rhabdomyolysis by co-administration of CPFX and atorvastatin (ATV) and to clarify the mechanisms of its pathogenesis. C57BL/6J mice treated with L-buthionine-( S, R )-sulfoximine (BSO), a glutathione synthesis inhibitor, were orally administered with CPFX and ATV for 4 days. Plasma levels of creatinine phosphokinase (CPK) and aspartate aminotransferase (AST) were significantly increased in the CPFX and ATV-co-administered group. Histopathological examination of skeletal muscle observed degeneration in gastrocnemius muscle and an increased number of the satellite cells. Expressions of skeletal muscle-specific microRNA and mRNA in plasma and skeletal muscle, respectively, were significantly increased. The area under the curve (AUC) of plasma CPFX was significantly increased in the CPFX and ATV-co-administered group. Furthermore, cytoplasmic vacuolization and a positively myoglobin-stained region in kidney tissue and high content of myoglobin in urine were observed. These results indicated that AKI was induced by myoglobin that leaked from skeletal muscle. The established mouse model in the present study would be useful for predicting potential rhabdomyolysis risks in preclinical drug development.