Febuxostat is a clinically approved xanthine oxidase inhibitor widely prescribed for hyperuricemia and gout. Because xanthine oxidase is a major source of reactive oxygen species, febuxostat is often considered beneficial in oxidative stress–driven disorders. However, rare reports linking febuxostat to rhabdomyolysis, particularly in patients with chronic kidney disease, raise concern that xanthine oxidase inhibition could aggravate muscle injury or accelerate acute kidney injury (AKI) during rhabdomyolysis. Whether febuxostat worsens acute muscle damage, kidney dysfunction, or cardiovascular impairment in this setting remains unclear. To address this knowledge gap, we tested the effects of an intraperitoneal dose of febuxostat (50 mg/kg) in adult male rats subjected to glycerol-induced rhabdomyolysis, with an emphasis on treatment timing. Febuxostat was administered 9 h or 6 h before intramuscular glycerol (50%) injection, or 6 h after glycerol challenge. Outcomes included renal hemodynamics (renal blood flow RBF, glomerular filtration rate GFR, renal vascular resistance RVR, renal resistive index RRI, and renal pulsatility index RPI), cardiac function, biochemical indices of muscle injury, and biomarkers of kidney and cardiac injury. Skeletal muscle and kidney histology were also assessed. Glycerol-induced rhabdomyolysis robustly activated the xanthine oxidase pathway, increasing circulating hypoxanthine/xanthine levels and plasma xanthine oxidase activity. Febuxostat effectively suppressed glycerol-induced increases in plasma xanthine oxidase activity and reduced uric acid levels. Moreover, febuxostat did not exacerbate biochemical injury markers, renal dysfunction, or histopathologic injury when given either before or after glycerol, supporting its safety during acute rhabdomyolysis. Notably, protection was strongly timing-dependent. Pretreatment, but not posttreatment, attenuated glycerol-induced increases in plasma creatine kinase, reduced myoglobinuria, decreased oxidative stress, and limited elevations in injury biomarkers. These benefits were accompanied by reduced skeletal muscle fiber disruption and less renal tubular injury on histological examination, indicating mitigation of both muscle and renal damage. Pretreatment also improved cardiac function, suggesting broader systemic benefit. Among pretreatment regimens, only the 9 h schedule meaningfully preserved renal function, improving RBF, GFR, RVR, RRI, and RPI, whereas 6 h pretreatment provided partial biochemical protection without comparable renal hemodynamic rescue. In contrast, posttreatment administered 6 h after glycerol failed to confer measurable benefit despite effective suppression of xanthine oxidase activity. Collectively, these findings demonstrate that febuxostat does not worsen rhabdomyolysis-associated acute muscle or kidney injury, while highlighting that efficacy depends on early administration. The results support the concept that xanthine oxidase activation amplifies early injury during rhabdomyolysis and that febuxostat may be most effective as a prophylactic or early-intervention strategy rather than rescue therapy once injury is established. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Michael et al. (Fri,) studied this question.