In vitro and in vivo metabolism of the anti-cancer agent CI-1040, a MEK inhibitor, in rat, monkey, and human.
OBJECTIVE
The use of in vitro and in vivo models using both rodent and non-rodent species plays an important role with regard to metabolism during the drug development process. In this study, we compared the metabolism of a MEK inhibitor (CI-1040) using in vitro and in vivo models with that observed in a cancer patient.


METHODS
Radiolabeled CI-1040 was assessed for metabolism using rat and monkey liver microsomes and hepatocytes, as well as in Wistar rats and cynomolgus monkeys via oral administration. Human bile and plasma samples were obtained immediately after administration of CI-1040 to a patient with advanced colon cancer. A combination of HPLC-radiochromatography (HPLC-RAM), LC/MS and LC/MS/MS experiments were used to analyze all resulting metabolites. Unlabeled CI-1040 was administered (100 mg/day, QD) for 15 days to a patient suffering from colon cancer. Bile was collected by the insertion of a T-tube directly into the bile duct over a 14-h period. Metabolites were also monitored in the patient's plasma.


RESULTS
Analysis of the metabolites in all species using in vitro and animal models demonstrated that CI-1040 undergoes extensive oxidative metabolism (14 metabolites identified) with subsequent glucuronidation of the hydroxylated metabolites. Metabolites were predominantly excreted through the bile in the animal models.


CONCLUSIONS
Overall, the in vitro and animal models in combination provided comprehensive coverage for all metabolites observed in human bile and plasma. In conclusion, the results obtained in this study demonstrate the utility of conducting investigations across species in order to gain complete coverage for successfully predicting human metabolites of new compounds in development.
Wabnitz
Paul A
PA
Department of Discovery Technologies, Pfizer Inc, Global Research and Development, Ann Arbor, Michigan, USA. paul.wabnitz@pfizer.com
Mitchell
David
D
Wabnitz
David A M
DA
D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000378:metabolism*; D001549:Benzamides / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D008956:Models, Chemical; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar
C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D020929:Mitogen-Activated Protein Kinase Kinases