Lenvatinib causes reduced expression of carnitine/organic cation transporter 2 and carnitine deficiency in the skeletal muscle of rats

• Published in: Toxicology letters Vol. 366; pp. 17 - 25
• Main Authors: Jing, Zheng, Okubo, Hironao, Morishige, Jun-ichi, Xu, Pingping, Hasan, Nazmul, Nagata, Naoto, Ando, Hitoshi
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.08.2022
• Subjects: Carnitine; Carnitine/organic cation transporter 2; Lenvatinib; Mitochondria; Skeletal muscle; Carnitine/organic cation transporter 2; CPT; HCC; OCTN; FGFR; Skeletal muscle; Carnitine; CACT; KIM-1; Mitochondria; TKI; mTOR; VEGFR; Lenvatinib
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2022.06.012

Lenvatinib, an oral tyrosine kinase inhibitor, is widely used to treat several types of advanced cancers but often causes muscular adverse reactions. Although carnitine supplementation may prevent these effects, the mechanism underlying lenvatinib-induced skeletal muscle impairment remains poorly understood. To this end, we aimed to investigate the impact of lenvatinib on carnitine disposition in rats. Once-daily administration of lenvatinib repeated for two weeks did not affect urinary excretion or serum concentration of carnitines throughout the treatment period but ultimately decreased the L-carnitine content in the skeletal muscle. The treatment decreased the expression of carnitine/organic cation transporter (OCTN) 2, a key transporter of carnitine, in skeletal muscle at the protein level but not at the mRNA level. In cultured C2C12 myocytes, lenvatinib inhibited OCTN2 expression in a dose-dependent manner at the protein level. Furthermore, lenvatinib dose-dependently decreased the protein levels of carnitine-related genes, adenosine triphosphate content, mitochondrial membrane potential, and markers of mitochondrial function in vitro. These results reveal the deleterious effects of lenvatinib on OCTN2 expression, carnitine content, and mitochondrial function in skeletal muscle that may be associated with muscle toxicity. •Lenvatinib reduces OCTN2 expression and carnitine content in the skeletal muscle.•Lenvatinib inhibits protein synthesis in C2C12 myocytes.•Lenvatinib impairs mitochondrial function in C2C12 myocytes.•These effects of lenvatinib may be involved in a subset of adverse reactions.