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Research ArticleArticle

In Vitro Metabolism of the Glucagon-Like Peptide-1 (GLP-1)–Derived Metabolites GLP-1(9-36)amide and GLP-1(28-36)amide in Mouse and Human Hepatocytes

Raman Sharma, Thomas S. McDonald, Heather Eng, Chris Limberakis, Benjamin D. Stevens, Sheena Patel and Amit S. Kalgutkar
Drug Metabolism and Disposition December 2013, 41 (12) 2148-2157; DOI: https://doi.org/10.1124/dmd.113.054254
Raman Sharma
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities (R.S., T.S.M., H.E.) and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry (C.L.), Pfizer, Inc., Groton, Connecticut; and Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities (A.S.K.), Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry (B.D.S.), and Cardiovascular, Metabolic and Endocrine Diseases Research Unit (S.P.), Pfizer, Inc, Cambridge, Massachusetts
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Thomas S. McDonald
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities (R.S., T.S.M., H.E.) and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry (C.L.), Pfizer, Inc., Groton, Connecticut; and Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities (A.S.K.), Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry (B.D.S.), and Cardiovascular, Metabolic and Endocrine Diseases Research Unit (S.P.), Pfizer, Inc, Cambridge, Massachusetts
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Heather Eng
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities (R.S., T.S.M., H.E.) and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry (C.L.), Pfizer, Inc., Groton, Connecticut; and Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities (A.S.K.), Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry (B.D.S.), and Cardiovascular, Metabolic and Endocrine Diseases Research Unit (S.P.), Pfizer, Inc, Cambridge, Massachusetts
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Chris Limberakis
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities (R.S., T.S.M., H.E.) and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry (C.L.), Pfizer, Inc., Groton, Connecticut; and Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities (A.S.K.), Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry (B.D.S.), and Cardiovascular, Metabolic and Endocrine Diseases Research Unit (S.P.), Pfizer, Inc, Cambridge, Massachusetts
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Benjamin D. Stevens
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities (R.S., T.S.M., H.E.) and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry (C.L.), Pfizer, Inc., Groton, Connecticut; and Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities (A.S.K.), Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry (B.D.S.), and Cardiovascular, Metabolic and Endocrine Diseases Research Unit (S.P.), Pfizer, Inc, Cambridge, Massachusetts
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Sheena Patel
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities (R.S., T.S.M., H.E.) and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry (C.L.), Pfizer, Inc., Groton, Connecticut; and Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities (A.S.K.), Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry (B.D.S.), and Cardiovascular, Metabolic and Endocrine Diseases Research Unit (S.P.), Pfizer, Inc, Cambridge, Massachusetts
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Amit S. Kalgutkar
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities (R.S., T.S.M., H.E.) and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry (C.L.), Pfizer, Inc., Groton, Connecticut; and Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities (A.S.K.), Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry (B.D.S.), and Cardiovascular, Metabolic and Endocrine Diseases Research Unit (S.P.), Pfizer, Inc, Cambridge, Massachusetts
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Abstract

Previous studies have revealed that the glucoincretin hormone glucagon-like peptide-1 (GLP-1)(7-36)amide is metabolized by dipeptidyl peptidase-IV (DPP-IV) and neutral endopeptidase 24.11 (NEP) to yield GLP-1(9-36)amide and GLP-1(28-36)amide, respectively, as the principal metabolites. Contrary to the previous notion that GLP-1(7-36)amide metabolites are pharmacologically inactive, recent studies have demonstrated cardioprotective and insulinomimetic effects with both GLP-1(9-36)amide and GLP-1(28-36)amide in animals and humans. In the present work, we examined the metabolic stability of the two GLP-1(7-36)amide metabolites in cryopreserved hepatocytes, which have been used to demonstrate the in vitro insulin-like effects of GLP-1(9-36)amide and GLP-1(28-36)amide on gluconeogenesis. To examine the metabolic stability of the GLP-1(7-36)amide metabolites, a liquid chromatography–tandem mass spectrometry assay was developed for the quantitation of the intact peptides in hepatocyte incubations. GLP-1(9-36)amide and GLP-1(28-36)amide were rapidly metabolized in mouse [GLP-1(9-36)amide: t1/2 = 52 minutes; GLP-1(28-36)amide: t1/2 = 13 minutes] and human hepatocytes [GLP-1(9-36)amide: t1/2 = 180 minutes; GLP-1(28-36)amide: t1/2 = 24 minutes), yielding a variety of N-terminal cleavage products that were characterized using mass spectrometry. Metabolism at the C terminus was not observed for either peptides. The DPP-IV and NEP inhibitors diprotin A and phosphoramidon, respectively, did not induce resistance in the two peptides toward proteolytic cleavage. Overall, our in vitro findings raise the intriguing possibility that the insulinomimetic effects of GLP-1(9-36)amide and GLP-1(28-36)amide on gluconeogenesis and oxidative stress might be due, at least in part, to the actions of additional downstream metabolites, which are obtained from the enzymatic cleavage of the peptide backbone in the parent compounds.

Footnotes

    • Received August 14, 2013.
    • Accepted September 20, 2013.
  • dx.doi.org/10.1124/dmd.113.054254.

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

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (12)
Drug Metabolism and Disposition
Vol. 41, Issue 12
1 Dec 2013
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Research ArticleArticle

Metabolism of GLP-1(9-36) and GLP-1(28-36) Amides

Raman Sharma, Thomas S. McDonald, Heather Eng, Chris Limberakis, Benjamin D. Stevens, Sheena Patel and Amit S. Kalgutkar
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2148-2157; DOI: https://doi.org/10.1124/dmd.113.054254

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Research ArticleArticle

Metabolism of GLP-1(9-36) and GLP-1(28-36) Amides

Raman Sharma, Thomas S. McDonald, Heather Eng, Chris Limberakis, Benjamin D. Stevens, Sheena Patel and Amit S. Kalgutkar
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2148-2157; DOI: https://doi.org/10.1124/dmd.113.054254
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