New insights into the vancomycin-induced nephrotoxicity using in vitro metabolomics combined with physiologically based pharmacokinetic modeling.

Vancomycin is a first-line treatment for invasive infections caused by multidrug-resistant gram-positive bacteria. However, vancomycin-induced nephrotoxicity is an increasing burden, particularly in patients with complex life-threatening conditions. Vancomycin-induced nephrotoxicity associated with clinically relevant exposure on the target site has not been well defined. This study aimed to acquire the concentration of vancomycin in the renal tubules and kidneys in humans using physiologically based pharmacokinetic (PBPK) modeling and simulation. Based upon the exposure of vancomycin in the renal tubule, the toxicity of vancomycin in human renal proximal tubular epithelial cells was examined with the XTT assay and in vitro metabolomics analysis. A rat PBPK model predicting plasma and kidney concentration-time profiles of vancomycin matched the observed behavior after a single administration of 10 mg/kg. The concentration of vancomycin in renal tubules was about 40-50 times higher than that in plasma. The human PBPK model transferred from the rat model predicted renal tubule concentrations of vancomycin as 316.1-2136.6 μg/mL at 500 mg every 6 hours, and 199.0-3932.5 μg/mL at 1000 mg every 12 hours. Vancomycin showed significant nephrotoxicity at 4 mg/mL in XTT assessment. In total, 11 lysophosphatidylcholines and one lysophosphatidylethanolamine were identified by metabolomics analysis. The concentration-dependent increase was evident in the release of lysophospholipids after vancomycin treatment (0.125-4 mg/mL) for 24 hours. Our study revealed the relationship between the exposure of vancomycin in the kidney and toxicity of vancomycin at clinically relevant concentrations achieved from a mechanical PBPK model. A series of lysophospholipids as potential metabolic markers of renal toxicity were identified.