Abstract

CPI-613, an inhibitor of pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (KGDH) enzymes, is currently in development for the treatment of pancreatic cancer (PANC), Acute Myeloid Leukemia (AML), and other cancers. CPI-613 is an analog of lipoic acid, an essential co-factor for both PDH and KGDH. Metabolism and mass balance studies were conducted in rats following IV 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 (V_max and K_m) of the metabolism of CPI-613 to these three metabolites predicted the fraction metabolized (fm) leading to the formation of M1, M2 and M3 to be 38, 6 and 56%, respectively. In humans, following IV 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 to that 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.