Metabolic biomarkers of aminoglycoside nephrotoxicity

Drug-induced nephrotoxicity is a limiting factor to the efficacy and safety of various therapeutics including the aminoglycoside antibiotics. Aminoglycosides, such as gentamicin, cause proximal tubule injury in a significant proportion of individuals they are given to. The onset of this adverse drug reaction is currently managed by the monitoring of serum peak and trough levels and measurement of the classic renal functional markers serum creatinine and blood urea nitrogen. The limitations of these biomarkers are well established but novel, sensitive proximal tubule-specific biomarkers, such as kidney injury molecule-1, are gradually coming to the fore. Still, management of aminoglycoside nephrotoxicity is lacking a personalised strategy whereby the risk of a patient developing proximal tubule injury can be established at the individual level before exposure. Prior studies of gentamicin nephrotoxicity pin-pointed that HMG-CoA reductase inhibitors, also known as statins, could inhibit the accumulation of gentamicin in vitro and therefore reduce the cytotoxicity of the drug. In order to study HMG-CoA reductase and its relationship to aminoglycoside accumulation further, an LC-MS/MS based assay was developed and validated to measure the product of the enzyme, mevalonic acid, in the urine of rats and humans. Urinary mevalonic acid was converted to mevalonolactone at pH 2, extracted alongside a deuterated internal standard using ethyl acetate and quantified by reversed-phase LC-MS/MS. The assay had a broad dynamic range of 0.0156–10 μg/mL with precisio