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.
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Authors | King C Lee, Robert Shorr, Robert Rodriguez, Claudia Maturo, Lakmal W Boteju, Adrian Sheldon |
Journal | Drug metabolism letters
(Drug Metab Lett)
Vol. 5
Issue 3
Pg. 163-82
(Aug 2011)
ISSN: 1874-0758 [Electronic] United Arab Emirates |
PMID | 21722089
(Publication Type: Journal Article)
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Chemical References |
- Antineoplastic Agents
- Caprylates
- Glucuronides
- Sulfides
- Sulfoxides
- devimistat
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Topics |
- Animals
- Antineoplastic Agents
(metabolism, pharmacology)
- Caprylates
(metabolism, pharmacology)
- Cell Line, Tumor
- Chromatography, Liquid
- Glucuronides
(metabolism)
- Half-Life
- Humans
- Liver
(metabolism)
- Mice
- Microsomes, Liver
(metabolism)
- Neoplasms
(drug therapy, pathology)
- Oxidation-Reduction
- Rats
- Rats, Sprague-Dawley
- Species Specificity
- Sulfides
(metabolism, pharmacology)
- Sulfoxides
(metabolism)
- Swine
- Swine, Miniature
- Tandem Mass Spectrometry
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