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Research ArticleArticle

In Vitro Characterization of Ertugliflozin Metabolism by UDP-Glucuronosyltransferase and Cytochrome P450 Enzymes

Kimberly Lapham, Ernesto Callegari, Julie Cianfrogna, Jian Lin, Mark Niosi, Christine C. Orozco, Raman Sharma and Theunis C. Goosen
Drug Metabolism and Disposition December 2020, 48 (12) 1350-1363; DOI: https://doi.org/10.1124/dmd.120.000171
Kimberly Lapham
Medicine Design, Pfizer Inc., Groton, Connecticut (K.L., E.C., J.L., M.N., C.C.O., R.S., T.C.G.) and Pfizer Inc., La Jolla, California (J.C.)
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Ernesto Callegari
Medicine Design, Pfizer Inc., Groton, Connecticut (K.L., E.C., J.L., M.N., C.C.O., R.S., T.C.G.) and Pfizer Inc., La Jolla, California (J.C.)
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Julie Cianfrogna
Medicine Design, Pfizer Inc., Groton, Connecticut (K.L., E.C., J.L., M.N., C.C.O., R.S., T.C.G.) and Pfizer Inc., La Jolla, California (J.C.)
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Jian Lin
Medicine Design, Pfizer Inc., Groton, Connecticut (K.L., E.C., J.L., M.N., C.C.O., R.S., T.C.G.) and Pfizer Inc., La Jolla, California (J.C.)
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Mark Niosi
Medicine Design, Pfizer Inc., Groton, Connecticut (K.L., E.C., J.L., M.N., C.C.O., R.S., T.C.G.) and Pfizer Inc., La Jolla, California (J.C.)
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Christine C. Orozco
Medicine Design, Pfizer Inc., Groton, Connecticut (K.L., E.C., J.L., M.N., C.C.O., R.S., T.C.G.) and Pfizer Inc., La Jolla, California (J.C.)
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Raman Sharma
Medicine Design, Pfizer Inc., Groton, Connecticut (K.L., E.C., J.L., M.N., C.C.O., R.S., T.C.G.) and Pfizer Inc., La Jolla, California (J.C.)
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Theunis C. Goosen
Medicine Design, Pfizer Inc., Groton, Connecticut (K.L., E.C., J.L., M.N., C.C.O., R.S., T.C.G.) and Pfizer Inc., La Jolla, California (J.C.)
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Abstract

Ertugliflozin is primarily cleared through UDP-glucurosyltransferase (UGT)–mediated metabolism (86%) with minor oxidative clearance (12%). In vitro phenotyping involved enzyme kinetic characterization of UGTs or cytochrome P450 enzymes catalyzing formation of the major 3-O-β-glucuronide (M5c) and minor 2-O-β-glucuronide (M5a), monohydroxylated ertugliflozin (M1 and M3), and des-ethyl ertugliflozin (M2) metabolites in human liver microsomes (HLMs). Fractional clearance (fCL) from HLM intrinsic clearance (CLint) indicated a major role for glucuronidation (fCL 0.96; CLint 37 µl/min per milligram) versus oxidative metabolism (fCL 0.04; CLint 1.64 µl/min per milligram). Substrate concentration at half-maximal velocity (Km), maximal rate of metabolism (Vmax), and CLint for M5c and M5a formation were 10.8 µM, 375 pmol/min per milligram, and 34.7 µl/min per milligram and 41.7 µM, 94.9 pmol/min per milligram, and 2.28 µl/min per milligram, respectively. Inhibition of HLM CLint with 10 µM digoxin or tranilast (UGT1A9) and 3 µM 16β-phenyllongifolol (UGT2B7/UGT2B4) resulted in fraction metabolism (fm) estimates of 0.81 and 0.19 for UGT1A9 and UGT2B7/UGT2B4, respectively. Relative activity factor scaling of recombinant enzyme kinetics provided comparable fm for UGT1A9 (0.86) and UGT2B7 (0.14). Km and Vmax for M1, M2, and M3 formation ranged 73.0–93.0 µM and 24.3–116 pmol/min per milligram, respectively, and was inhibited by ketoconazole (M1, M2, and M3) and montelukast (M2). In summary, ertugliflozin metabolism in HLMs was primarily mediated by UGT1A9 (78%) with minor contributions from UGT2B7/UGT2B4 (18%), CYP3A4 (3.4%), CYP3A5 (0.4%), and CYP2C8 (0.16%). Considering higher ertugliflozin oxidative metabolism (fCL 0.12) obtained from human mass balance, human systemic clearance is expected to be mediated by UGT1A9 (70%), UGT2B7/UGT2B4 (16%), CYP3A4 (10%), CYP3A5 (1.2%), CYP2C8 (0.5%), and renal elimination (2%).

SIGNIFICANCE STATEMENT This manuscript describes the use of orthogonal approaches (i.e., enzyme kinetics, chemical inhibitors, and recombinant enzymes) to characterize the fraction of ertugliflozin metabolism through various UDP-glucuronosyltransferase (UGT) and cytochrome P450 (CYP) enzyme-mediated pathways. Phenotyping approaches routinely used to characterize CYP hepatic fractional metabolism (fm) to estimate specific enzymes contributing to overall systemic clearance were similarly applied for UGT-mediated metabolism. Defining the in vitro metabolic disposition and fm for ertugliflozin allows risk assessment when considering potential victim-based drug-drug interactions perpetrated by coadministered drugs.

Footnotes

    • Received July 6, 2020.
    • Accepted September 22, 2020.
  • This study was sponsored by Pfizer Inc., New York, NY in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ.

  • A portion of this work was presented as a poster at the 22nd North American International Society for the Study of Xenobiotics Meeting; (2018) in Montréal, Canada.

  • L.P., E.C., J.C., J.L., M.N., C.C.O., R.S., and T.C.G. are employees of Pfizer Inc., New York, NY and may own shares/stock options in Pfizer Inc., New York, NY.

  • https://doi.org/10.1124/dmd.120.000171.

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

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 48 (12)
Drug Metabolism and Disposition
Vol. 48, Issue 12
1 Dec 2020
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Research ArticleArticle

Ertugliflozin Phenotyping

Kimberly Lapham, Ernesto Callegari, Julie Cianfrogna, Jian Lin, Mark Niosi, Christine C. Orozco, Raman Sharma and Theunis C. Goosen
Drug Metabolism and Disposition December 1, 2020, 48 (12) 1350-1363; DOI: https://doi.org/10.1124/dmd.120.000171

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Research ArticleArticle

Ertugliflozin Phenotyping

Kimberly Lapham, Ernesto Callegari, Julie Cianfrogna, Jian Lin, Mark Niosi, Christine C. Orozco, Raman Sharma and Theunis C. Goosen
Drug Metabolism and Disposition December 1, 2020, 48 (12) 1350-1363; DOI: https://doi.org/10.1124/dmd.120.000171
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