LAUSR

CPI-613, an inhibitor of pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (KGDH) enzymes, is currently in development for the treatment of pancreatic cancer, acute myeloid leukemia, and other cancers. CPI-613 is an analog of lipoic acid, an essential cofactor for both PDH and KGDH. Metabolism and mass balance studies were conducted in rats after intravenous administration of [14C]-CPI-613. CPI-613 was eliminated via oxidative metabolism followed by excretion of the metabolites in feces (59%) and urine (22%). β-Oxidation was the major pathway of elimination for CPI-613. The most abundant circulating components in rat plasma were those derived from β-oxidation. In human hepatocytes, CPI-613 mainly underwent β-oxidation (M1), sulfur oxidation (M2), and glucuronidation (M3). The Michaelis-Menten kinetics (Vmax and Km) of the metabolism of CPI-613 to these three metabolites predicted the fraction metabolized leading to the formation of M1, M2, and M3 to be 38%, 6%, and 56%, respectively. In humans, after intravenous administration of CPI-613, major circulating species in plasma were the parent and the β-oxidation derived products. Thus, CPI-613 metabolites profiles in rat and human plasma were qualitatively similar. β-Oxidation characteristics and excretion patterns of CPI-613 are discussed in comparison with those reported for its endogenous counterpart, lipoic acid. SIGNIFICANCE STATEMENT This work highlights the clearance mechanism of CPI-613 via β-oxidation, species differences in their ability to carry out β-oxidation, and subsequent elimination routes. Structural limitations for completion of terminal cycle of β-oxidation is discussed against the backdrop of its endogenous counterpart lipoic acid.