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Research ArticleArticle

Metabolism and Excretion of Canagliflozin in Mice, Rats, Dogs, and Humans

Rao N. V. S. Mamidi, Filip Cuyckens, Jie Chen, Ellen Scheers, Dennis Kalamaridis, Ronghui Lin, Jose Silva, Sue Sha, David C. Evans, Michael F. Kelley, Damayanthi Devineni, Mark D. Johnson and Heng Keang Lim
Drug Metabolism and Disposition May 2014, 42 (5) 903-916; DOI: https://doi.org/10.1124/dmd.113.056440
Rao N. V. S. Mamidi
Janssen Research & Development, Raritan, New Jersey (R.N.V.S.M., S.S., D.D., M.D.J.), Janssen Research & Development, Spring House, Pennsylvania (J.C., D.K., R.L., J.S., D.C.E., M.F.K., H.K.L.), and Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium (F.C., E.S.)
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Filip Cuyckens
Janssen Research & Development, Raritan, New Jersey (R.N.V.S.M., S.S., D.D., M.D.J.), Janssen Research & Development, Spring House, Pennsylvania (J.C., D.K., R.L., J.S., D.C.E., M.F.K., H.K.L.), and Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium (F.C., E.S.)
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Jie Chen
Janssen Research & Development, Raritan, New Jersey (R.N.V.S.M., S.S., D.D., M.D.J.), Janssen Research & Development, Spring House, Pennsylvania (J.C., D.K., R.L., J.S., D.C.E., M.F.K., H.K.L.), and Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium (F.C., E.S.)
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Ellen Scheers
Janssen Research & Development, Raritan, New Jersey (R.N.V.S.M., S.S., D.D., M.D.J.), Janssen Research & Development, Spring House, Pennsylvania (J.C., D.K., R.L., J.S., D.C.E., M.F.K., H.K.L.), and Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium (F.C., E.S.)
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Dennis Kalamaridis
Janssen Research & Development, Raritan, New Jersey (R.N.V.S.M., S.S., D.D., M.D.J.), Janssen Research & Development, Spring House, Pennsylvania (J.C., D.K., R.L., J.S., D.C.E., M.F.K., H.K.L.), and Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium (F.C., E.S.)
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Ronghui Lin
Janssen Research & Development, Raritan, New Jersey (R.N.V.S.M., S.S., D.D., M.D.J.), Janssen Research & Development, Spring House, Pennsylvania (J.C., D.K., R.L., J.S., D.C.E., M.F.K., H.K.L.), and Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium (F.C., E.S.)
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Jose Silva
Janssen Research & Development, Raritan, New Jersey (R.N.V.S.M., S.S., D.D., M.D.J.), Janssen Research & Development, Spring House, Pennsylvania (J.C., D.K., R.L., J.S., D.C.E., M.F.K., H.K.L.), and Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium (F.C., E.S.)
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Sue Sha
Janssen Research & Development, Raritan, New Jersey (R.N.V.S.M., S.S., D.D., M.D.J.), Janssen Research & Development, Spring House, Pennsylvania (J.C., D.K., R.L., J.S., D.C.E., M.F.K., H.K.L.), and Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium (F.C., E.S.)
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David C. Evans
Janssen Research & Development, Raritan, New Jersey (R.N.V.S.M., S.S., D.D., M.D.J.), Janssen Research & Development, Spring House, Pennsylvania (J.C., D.K., R.L., J.S., D.C.E., M.F.K., H.K.L.), and Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium (F.C., E.S.)
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Michael F. Kelley
Janssen Research & Development, Raritan, New Jersey (R.N.V.S.M., S.S., D.D., M.D.J.), Janssen Research & Development, Spring House, Pennsylvania (J.C., D.K., R.L., J.S., D.C.E., M.F.K., H.K.L.), and Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium (F.C., E.S.)
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Damayanthi Devineni
Janssen Research & Development, Raritan, New Jersey (R.N.V.S.M., S.S., D.D., M.D.J.), Janssen Research & Development, Spring House, Pennsylvania (J.C., D.K., R.L., J.S., D.C.E., M.F.K., H.K.L.), and Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium (F.C., E.S.)
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Mark D. Johnson
Janssen Research & Development, Raritan, New Jersey (R.N.V.S.M., S.S., D.D., M.D.J.), Janssen Research & Development, Spring House, Pennsylvania (J.C., D.K., R.L., J.S., D.C.E., M.F.K., H.K.L.), and Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium (F.C., E.S.)
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Heng Keang Lim
Janssen Research & Development, Raritan, New Jersey (R.N.V.S.M., S.S., D.D., M.D.J.), Janssen Research & Development, Spring House, Pennsylvania (J.C., D.K., R.L., J.S., D.C.E., M.F.K., H.K.L.), and Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium (F.C., E.S.)
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Abstract

Canagliflozin is an oral antihyperglycemic agent used for the treatment of type 2 diabetes mellitus. It blocks the reabsorption of glucose in the proximal renal tubule by inhibiting the sodium-glucose cotransporter 2. This article describes the in vivo biotransformation and disposition of canagliflozin after a single oral dose of [14C]canagliflozin to intact and bile duct-cannulated (BDC) mice and rats and to intact dogs and humans. Fecal excretion was the primary route of elimination of drug-derived radioactivity in both animals and humans. In BDC mice and rats, most radioactivity was excreted in bile. The extent of radioactivity excreted in urine as a percentage of the administered [14C]canagliflozin dose was 1.2%–7.6% in animals and approximately 33% in humans. The primary pathways contributing to the metabolic clearance of canagliflozin were oxidation in animals and direct glucuronidation of canagliflozin in humans. Unchanged canagliflozin was the major component in systemic circulation in all species. In human plasma, two pharmacologically inactive O-glucuronide conjugates of canagliflozin, M5 and M7, represented 19% and 14% of total drug-related exposure and were considered major human metabolites. Plasma concentrations of M5 and M7 in mice and rats from repeated dose safety studies were lower than those in humans given canagliflozin at the maximum recommended dose of 300 mg. However, biliary metabolite profiling in rodents indicated that mouse and rat livers had significant exposure to M5 and M7. Pharmacologic inactivity and high water solubility of M5 and M7 support glucuronidation of canagliflozin as a safe detoxification pathway.

Footnotes

    • Received December 11, 2013.
    • Accepted February 25, 2014.
  • dx.doi.org/10.1124/dmd.113.056440.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (5)
Drug Metabolism and Disposition
Vol. 42, Issue 5
1 May 2014
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Research ArticleArticle

In Vivo Metabolism of Canagliflozin in Animals and Humans

Rao N. V. S. Mamidi, Filip Cuyckens, Jie Chen, Ellen Scheers, Dennis Kalamaridis, Ronghui Lin, Jose Silva, Sue Sha, David C. Evans, Michael F. Kelley, Damayanthi Devineni, Mark D. Johnson and Heng Keang Lim
Drug Metabolism and Disposition May 1, 2014, 42 (5) 903-916; DOI: https://doi.org/10.1124/dmd.113.056440

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Research ArticleArticle

In Vivo Metabolism of Canagliflozin in Animals and Humans

Rao N. V. S. Mamidi, Filip Cuyckens, Jie Chen, Ellen Scheers, Dennis Kalamaridis, Ronghui Lin, Jose Silva, Sue Sha, David C. Evans, Michael F. Kelley, Damayanthi Devineni, Mark D. Johnson and Heng Keang Lim
Drug Metabolism and Disposition May 1, 2014, 42 (5) 903-916; DOI: https://doi.org/10.1124/dmd.113.056440
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