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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

XP13512 [(±)-1-([(α-Isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane Acetic Acid], A Novel Gabapentin Prodrug: I. Design, Synthesis, Enzymatic Conversion to Gabapentin, and Transport by Intestinal Solute Transporters

Kenneth C. Cundy, Russell Branch, Tania Chernov-Rogan, Tracy Dias, Toño Estrada, Karin Hold, Kerry Koller, Xiaoli Liu, Adam Mann, Matt Panuwat, Stephen P. Raillard, Shubhra Upadhyay, Quincey Q. Wu, Jia-Ning Xiang, Hui Yan, Noa Zerangue, Cindy X. Zhou, Ronald W. Barrett and Mark A. Gallop
Journal of Pharmacology and Experimental Therapeutics October 2004, 311 (1) 315-323; DOI: https://doi.org/10.1124/jpet.104.067934
Kenneth C. Cundy
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Russell Branch
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Tania Chernov-Rogan
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Tracy Dias
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Toño Estrada
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Karin Hold
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Kerry Koller
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Xiaoli Liu
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Adam Mann
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Matt Panuwat
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Stephen P. Raillard
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Shubhra Upadhyay
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Quincey Q. Wu
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Jia-Ning Xiang
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Hui Yan
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Noa Zerangue
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Cindy X. Zhou
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Ronald W. Barrett
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Mark A. Gallop
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Abstract

Gabapentin is thought to be absorbed from the intestine of humans and animals by a low-capacity solute transporter localized in the upper small intestine. Saturation of this transporter at doses used clinically leads to dose-dependent pharmacokinetics and high interpatient variability, potentially resulting in suboptimal drug exposure in some patients. XP13512 [(±)-1-([(α-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid] is a novel prodrug of gabapentin designed to be absorbed throughout the intestine by high-capacity nutrient transporters. XP13512 was stable at physiological pH but rapidly converted to gabapentin in intestinal and liver tissue from rats, dogs, monkeys, and humans. XP13512 was not a substrate or inhibitor of major cytochrome P450 isoforms in transfected baculosomes or liver homogenates. The separated isomers of XP13512 showed similar cleavage in human tissues. The prodrug demonstrated active apical to basolateral transport across Caco-2 cell monolayers and pH-dependent passive permeability across artificial membranes. XP13512 inhibited uptake of 14C-lactate by human embryonic kidney cells expressing monocarboxylate transporter type-1, and direct uptake of prodrug by these cells was confirmed using liquid chromatography-tandem mass spectrometry. XP13512 inhibited uptake of 3H-biotin into Chinese hamster ovary cells overexpressing human sodium-dependent multivitamin transporter (SMVT). Specific transport by SMVT was confirmed by oocyte electrophysiology studies and direct uptake studies in human embryonic kidney cells after tetracycline-induced expression of SMVT. XP13512 is therefore a substrate for several high-capacity absorption pathways present throughout the intestine. Therefore, administration of the prodrug should result in improved gabapentin bioavailability, dose proportionality, and colonic absorption compared with administration of gabapentin.

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

  • doi:10.1124/jpet.104.067934.

  • ABBREVIATIONS: XP13512, (±)-1-([(α-isobutanoyloxyethoxy)carbonyl]aminomethyl)-1-cyclohexane acetic acid; MCT-1, monocarboxylate transporter type-1; SMVT, sodium-dependent multivitamin transporter; LC/MS/MS, liquid chromatography-tandem mass spectrometry; P450, cytochrome P450; PCR, polymerase chain reaction; HEK, human embryonic kidney; CHO, Chinese hamster ovary; MDCK, Madin-Darby canine kidney; HBSS, Hanks' balanced salt solution; Papp, apparent permeability value; Pam, artificial membrane permeability value; LAT1, L-type amino acid transporter.

    • Received March 5, 2004.
    • Accepted May 14, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 311 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 311, Issue 1
1 Oct 2004
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XP13512 [(±)-1-([(α-Isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane Acetic Acid], A Novel Gabapentin Prodrug: I. Design, Synthesis, Enzymatic Conversion to Gabapentin, and Transport by Intestinal Solute Transporters
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

XP13512 [(±)-1-([(α-Isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane Acetic Acid], A Novel Gabapentin Prodrug: I. Design, Synthesis, Enzymatic Conversion to Gabapentin, and Transport by Intestinal Solute Transporters

Kenneth C. Cundy, Russell Branch, Tania Chernov-Rogan, Tracy Dias, Toño Estrada, Karin Hold, Kerry Koller, Xiaoli Liu, Adam Mann, Matt Panuwat, Stephen P. Raillard, Shubhra Upadhyay, Quincey Q. Wu, Jia-Ning Xiang, Hui Yan, Noa Zerangue, Cindy X. Zhou, Ronald W. Barrett and Mark A. Gallop
Journal of Pharmacology and Experimental Therapeutics October 1, 2004, 311 (1) 315-323; DOI: https://doi.org/10.1124/jpet.104.067934

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

XP13512 [(±)-1-([(α-Isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane Acetic Acid], A Novel Gabapentin Prodrug: I. Design, Synthesis, Enzymatic Conversion to Gabapentin, and Transport by Intestinal Solute Transporters

Kenneth C. Cundy, Russell Branch, Tania Chernov-Rogan, Tracy Dias, Toño Estrada, Karin Hold, Kerry Koller, Xiaoli Liu, Adam Mann, Matt Panuwat, Stephen P. Raillard, Shubhra Upadhyay, Quincey Q. Wu, Jia-Ning Xiang, Hui Yan, Noa Zerangue, Cindy X. Zhou, Ronald W. Barrett and Mark A. Gallop
Journal of Pharmacology and Experimental Therapeutics October 1, 2004, 311 (1) 315-323; DOI: https://doi.org/10.1124/jpet.104.067934
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