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Research ArticleArticle

Transepithelial Transport of the Group II Metabotropic Glutamate 2/3 Receptor Agonist (1S,2S,5R,6S)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY354740) and Its Prodrug (1S,2S,5R,6S)-2-[(2′S)-(2′-Amino)propionyl]aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY544344)

Manthena V. S. Varma, André H. Eriksson, Geri Sawada, Youngeen A. Pak, Everett J. Perkins and Cheryl L. Zimmerman
Drug Metabolism and Disposition January 2009, 37 (1) 211-220; DOI: https://doi.org/10.1124/dmd.108.022012
Manthena V. S. Varma
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André H. Eriksson
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Geri Sawada
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Youngeen A. Pak
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Everett J. Perkins
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Cheryl L. Zimmerman
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Abstract

The limited oral bioavailability of the potent and selective group II metabotropic glutamate (mGlu) 2/3 receptor agonist, (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY354740), was shown to be improved by its peptidyl prodrug, (1S,2S,5R,6S)-2-[(2′S)-(2′-amino)propionyl]aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY544344). The purpose of this study was to elucidate the mechanisms of intestinal absorption of LY354740 and its prodrug LY544344. Transepithelial transport and accumulation studies were performed in Caco-2 cell monolayers; the involvement of the peptide transporter 1 (PEPT1) transporter was also examined. In absorptive transport studies, the peptidyl prodrug LY544344 partially hydrolyzed to release LY354740 intracellularly, and both compounds appeared in the basolateral compartment. The absorptive transport rate of LY544344, basolateral appearance rate of LY354740, and their cellular accumulation after incubation with LY544344 were concentration-dependent. PEPT1 inhibition reduced transepithelial transport and cellular accumulation of LY544344 to 22 and 1.1% of control, respectively. LY354740 showed concentration-independent absorptive transport with negligible cellular accumulation. Efflux and trans-stimulation studies revealed predominantly apical efflux and the existence of specific transporters for LY544344 and intracellularly released LY354740 on the apical and basolateral membranes. LY544344 efflux was also trans-stimulated at the apical side by glycyl-glutamate but not by glycyl-sarcosine. Transport of neither compound was affected by P-glycoprotein-mediated efflux, as shown in transport and uptake inhibition studies in Madin-Darby canine kidney multidrug resistance 1-transfected cell line and inverted membrane vesicles. In conclusion, LY354740 is mainly transported by the paracellular pathway, whereas intestinal absorption of LY544344 is mediated by PEPT1. However, the absorptive transport of LY544344 seems to be modulated by an apical efflux transporter and a rate-limiting transport step across the basolateral membrane.

Footnotes

  • This project was supported by Eli Lilly and Company, Indianapolis, IN.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.022012.

  • ABBREVIATIONS: mGlu, group II metabotropic glutamate; LY354740, (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate; PEPT1, peptide transporter 1; LY544344, (1S,2S,5R,6S)-2-[(2′S)-(2′-amino)propionyl]aminobicyclo[3.1.0]hexane-2,6-dicarboxylate; MDR, multidrug resistance; PEAK-MDR1, transformed human embryonic kidney cells stably overexpressing MDR1; MDCKII, Madin-Darby canine kidney; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; LSN335984, (R)-4-((1aR,6R,10bS)-1,2-dichloro-1,1a,6,10b-tetrahydrodibenzo(a,e)-cyclopropa(c)cycloheptan-6-yl)-α-((5-quinoloyloxy)methyl)-1-piperazineethanol, trihydrochloride; HPLC, high-performance liquid chromatography; GlySar, glycyl-sarcosine; GlyGlu, glycyl-glutamate; AMP-PNP, adenylyl-imidodiphosphate tetrasodium salt; RH, relative humidity; TEER, transepithelial electric resistance; WT, wild type; HBSS, Hanks' balanced salt solution; A-to-B, apical-to-basolateral; B-to-A, basolateral-to-apical; PBS, phosphate-buffered saline; LC, liquid chromatography; P-gp, P-glycoprotein.

  • ↵1 Current affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut.

  • ↵2 Current affiliation: Bioneer:FARMA, Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Received April 23, 2008.
    • Accepted October 2, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (1)
Drug Metabolism and Disposition
Vol. 37, Issue 1
1 Jan 2009
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Transepithelial Transport of the Group II Metabotropic Glutamate 2/3 Receptor Agonist (1S,2S,5R,6S)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY354740) and Its Prodrug (1S,2S,5R,6S)-2-[(2′S)-(2′-Amino)propionyl]aminobicyclo[3.1.0]hexane-2,6-dicarbox…
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Research ArticleArticle

Transepithelial Transport of the Group II Metabotropic Glutamate 2/3 Receptor Agonist (1S,2S,5R,6S)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY354740) and Its Prodrug (1S,2S,5R,6S)-2-[(2′S)-(2′-Amino)propionyl]aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY544344)

Manthena V. S. Varma, André H. Eriksson, Geri Sawada, Youngeen A. Pak, Everett J. Perkins and Cheryl L. Zimmerman
Drug Metabolism and Disposition January 1, 2009, 37 (1) 211-220; DOI: https://doi.org/10.1124/dmd.108.022012

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Research ArticleArticle

Transepithelial Transport of the Group II Metabotropic Glutamate 2/3 Receptor Agonist (1S,2S,5R,6S)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY354740) and Its Prodrug (1S,2S,5R,6S)-2-[(2′S)-(2′-Amino)propionyl]aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY544344)

Manthena V. S. Varma, André H. Eriksson, Geri Sawada, Youngeen A. Pak, Everett J. Perkins and Cheryl L. Zimmerman
Drug Metabolism and Disposition January 1, 2009, 37 (1) 211-220; DOI: https://doi.org/10.1124/dmd.108.022012
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