Drug Metabolism Letters

Zhiyang Zhao
Amgen
Cambridge, MA
USA

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Formation and Anti-Tumor Activity of Uncommon In Vitro and In Vivo Metabolites of CPI-613, a Novel Anti-Tumor Compound That Selectively Alters Tumor Energy Metabolism

Author(s): King C. Lee, Robert Shorr, Robert Rodriguez, Claudia Maturo, Lakmal W. Boteju, Adrian Sheldon.

Abstract:

CPI-613 is a novel anti-tumor compound with a mechanism-of-action which appears distinct from the current classes of anti-cancer agents used in the clinic. CPI-613 demonstrates both in vitro and in vivo anti-tumor activity. In vitro metabolic studies using liver S9 were performed which demonstrated that CPI-613 undergoes both phase 1 (oxidation) and phase 2 (glucuronidation) transformations. Its metabolic half-life varied between species and ranged from 8 minutes (Hanford minipig) to 47 minutes (CD-1 mouse).

We performed metabolite mass assessments using selected in vitro incubation samples and demonstrated that +16 amu oxidation with and without +176 amu glucuronidation products were generated by human and animal liver S9. LC/MS/MS fragmentation patterns showed that an uncommon sulfoxide metabolite was formed and the O-glucuronidation occurred at the terminal carboxyl moiety. We observed that the +192 amu sulfoxide/glucuronide was generated only in human liver S9 and not by any of the other species tested.

Synthetic metabolites were prepared and compared with the enzymatically-generated metabolites. Both the chromatographic retention times and the LC/MS/MS fragmentation patterns were similar, demonstrating that the synthetic metabolites were virtually identical to the S9-generated products. CYP450 reaction phenotyping and inhibition data both suggested that multiple CYP isozymes (2C8 and 3A4, along with minor contributions by 2C9 and 2C19) were involved in CPI-613 metabolism and sulfoxide formation.

Plasma samples from human subjects dosed with CPI-613 also contained the sulfoxide ± glucuronide metabolites. These results show that the in vitro- and in vivo-generated phase 1 and phase 2 metabolites were in good agreement.

Keywords: CPI-613, Metabolite, Sulfoxide, Glucuronidation, Anti-tumor, Tumor Energy Metabolism, LC/MS/MS, Pyruvate Dehydrogenase (PDC), alpha-ketoglutarate dehydrogenase (KDH), hypoxic

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Article Details

VOLUME: 5
ISSUE: 3
Year: 2011
Page: [163 - 182]
Pages: 20
DOI: 10.2174/187231211796904991
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