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Disposition and Metabolism of the Angiogenic Moderator O-(Chloroacetyl-carbamoyl) Fumagillol (TNP-470; AGM-1470) in Human Hepatocytes and Tissue Microsomes¹

Department of Pharmacology, Center for AIDS Research, Comprehensive Cancer Center, Division of Clinical Pharmacology, University of Alabama at Birmingham, Birmingham, Alabama 35294 [L. P., E. C-S., M. P., J-P. S.], and Centre de Recherche Agronomique, Equipe INSERM, 41 bd du Cap, BP 2078-06606 Antibes, Cedex, France [G. S., R. R.]

The biotransformation of O-(chloroacetyl-carbamoyl) fumagillol (TNP-470; AGM 1470), a potent in vitro inhibitor of angiogenesis, was investigated in primary cultured human hepatocytes and microsomal fractions of various human tissues. Exposure of human hepatocytes to 5 µM [³H]TNP-470 led to a rapid metabolism of unchanged drug to six metabolic derivatives within 30 min. The predominant extracellular metabolites were M-II and M-IV, attaining a maximum level of 3.23 ± 0.34 and 0.88 ± 0.10 µM, respectively. M-II leveled off, while M-IV rapidly declined to 0.06 ± 0.05 µM by 3 h. TNP-470 was undetectable after 60 min. M-V and M-VI slowly reached maximal concentrations of 0.26 ± 0.12 and 0.32 ± 0.16 µM, respectively. M-I only reached a concentration of 0.18 ± 0.07 µM at 60 min and leveled at 0.13 ± 0.06 µM for the remaining time of the experiment. The intracellular profile was different, with M-III and M-V representing the major metabolites detected. Studies using human liver microsomes demonstrated that M-IV formation was associated with an esterase-like enzymatic cleavage of TNP-470 and that this metabolite was then further metabolized by microsomal epoxide hydrolase to M-II, as evidenced by inhibition of this metabolic step by cyclohexene oxide, a microsomal epoxide hydrolase inhibitor. Extrahepatic metabolism of TNP-470 was also demonstrated using different sites of human intestinal, stomach, and kidney microsomes, with metabolite M-IV as the principal derivative detected in these tissues. Hepatic microsomal samples from seven different donors demonstrated large interindividual variations in the formation of both M-II and M-IV. In summary, this study demonstrates a rapid and extensive metabolism of TNP-470 in human tissues. The data emphasize the need to evaluate the in vivo formation and extent of TNP-470 metabolites to adequately assess the pharmacodynamic effects of this novel anticancer drug with a novel mechanism of action.

¹ This work was supported in part by USPHS Grant AI-32775 and by an unrestricted grant from TAP Pharmaceuticals, Inc. J-P. S. is a recipient of a Faculty Research Award from the American Cancer Society.

² To whom requests for reprints should be addressed, at Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 1670 University Boulevard, Volker Hall G019, Birmingham, AL 35294.

Received 3/ 9/95. Accepted 5/16/95.

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