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, 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.
Footnotes
- Received October 11, 2021.
- Accepted January 20, 2022.
This work received no external funding.
V.B.R., L.B., A.B., N.R., J.H., and S.L. are paid employees of Rafael Pharmaceuticals Inc. L.S., K.K., and A.S. are paid employees of contract research organizations Frontage Laboratories or Charles River Laboratories.
- Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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β-Oxidation of CPI-613 in Rat and Human
