[Aim] Lenvatinib (LEN) is an oral tyrosine kinase inhibitor used for the treatment of thyroid cancer and hepatocellular carcinoma. Although fatigue is a common adverse reaction resulting in discontinuation of LEN, the mechanism underlying its development remains poorly understood. To address this issue, we investigated the effect of LEN on carnitine disposition and mitochondrial damage.

[Methods] Male Wistar rats were orally administered with vehicle or LEN (0.2 or 2 mg/kg) once daily for 14 days. In vitro experiments, differentiated C2C12 myotube cells were cultured with or without LEN (10 nM­­­–10 µM) for 24 hours.

[Results] Treatment with LEN did not affect serum concentration and urinary excretion of carnitine, but decreased mRNA and protein expression levels of CPT1, CPT2, CACT and OXPHOS in the skeletal muscles, but not the kidney, of rats. Consistently, LEN caused cell death and decreased mitochondrial protein expression in C2C12 cells in a dose-dependent manner.

[Conclusion] LEN may directly cause mitochondrial impairment in the skeletal muscle, suggesting one possible mechanism for the development of fatigue.