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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION
Department of Pharmacy Practice, Purdue University, Indianapolis, Indiana (S.K.Q.); Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana (S.P.S., W.I.D., T.D.H., Z.S., W.F.B.); and University of Iowa, College of Pharmacy, Iowa City, Iowa (D.J.M.)
Capecitabine is an oral prodrug of 5-fluorouracil that is indicated for the treatment of breast and colorectal cancers. A three-step in vivo-targeted activation process requiring carboxylesterases, cytidine deaminase, and thymidine phosphorylase converts capecitabine to 5-fluorouracil. Carboxylesterases hydrolyze capecitabine's carbamate side chain to form 5'-deoxy-5-fluorocytidine (5'-DFCR). This study examines the steady-state kinetics of recombinant human carboxylesterase isozymes carboxylesterase (CES) 1A1, CES2, and CES3 for hydrolysis of capecitabine with a liquid chromatography/mass spectroscopy assay. Additionally, a spectrophotometric screening assay was utilized to identify drugs that may inhibit carboxylesterase activation of capecitabine. CES1A1 and CES2 hydrolyze capecitabine to a similar extent, with catalytic efficiencies of 14.7 and 12.9 min–1 mM–1, respectively. Little catalytic activity is detected for CES3 with capecitabine. Northern blot analysis indicates that relative expression in intestinal tissue is CES2 > CES1A1 > CES3. Hence, intestinal activation of capecitabine may contribute to its efficacy in colon cancer and toxic diarrhea associated with the agent. Loperamide is a strong inhibitor of CES2, with a Ki of 1.5 µM, but it only weakly inhibits CES1A1 (IC50 = 0.44 mM). Inhibition of CES2 in the gastrointestinal tract by loperamide may reduce local formation of 5'-DFCR. Both CES1A1 and CES2 are responsible for the activation of capecitabine, whereas CES3 plays little role in 5'-DFCR formation.
Address correspondence to: Dr. William F. Bosron, Biotechnology Research and Training Center, Indiana University School of Medicine, 1345 W. 16th Street, Room L3-304, Indianapolis, IN 46202. E-mail: wbosron{at}iupui.edu
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