A metabolic profiling analysis of the nephrotoxicity of acyclovir in rats using ultra performance liquid chromatography/mass spectrometry

•Our metabonomics analysis provided an approach for elucidating ACV induced nephrotoxicity.•ACV can induce nephrotoxicity within a certain range of treating time and dose.•We found multiple metabolites related to renal injury.•Findings found that guanine is one of ACV’s metabolic products related to ACV induced nephrotoxicity.

Acyclovir (ACV) exposure is a common cause of acute kidney injury (AKI). The toxicity mechanism of ACV has always been a matter of debate. The present study investigated into the time-effect relationship and dose-effect relationship of ACV-induced nephrotoxicity in rats using metabonomics. Twenty-four rats were randomly divided into four groups: a 0.9% NaCl solution group, and 100, 300, and 600 mg/kg ACV-treated groups; the ACV or vehicle solution was administered with a single intravenous injection. Urine was collected at different time periods (12 h before administration, and 0–6 h, 7–12 h, and 13–24 h after administration). Routine urinalysis was conducted by a urine automatic analyzer. Renal markers, including urine urea nitrogen, urine creatinine, and urinary N-acetyl-β-d-glucosaminidase (NAG) activity, were determined using established protocols. Urinary metabolites were evaluated using ultra performance liquid chromatography/mass spectrometry (UPLC/MS). In the ACV-treated rats, increased levels of protein (PRO), occult blood (BLD), white blood cell (WBC), and NAG activity in urine were observed, while the urine creatinine and urea nitrogen levels showed a decrease compared with the control. Moreover, urine metabolites significantly changed after the treatment with ACV, and all the effects induced by ACV were dose–time dependent. Finally, 4 metabolites (guanine, 4-guanidinobutyric acid, creatinine, and urea) were identified, which can be used for further research on the mechanism of ACV-induced nephrotoxicity.