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

Cundy, Kenneth C.; Branch, Russell; Chernov-Rogan, Tania; Dias, Tracy; Estrada, Toño; Höld, Karin M.; Koller, Kerry J.; Liu, Xiaoli; Mann, Adam; Panuwat, Matt; Raillard, Stephen P.; Upadhyay, Shubhra; Wu, Quincey Q.; Xiang, Jia‐Ning; Yan, Hui; Zerangue, Noa; Zhou, Cindy; Barrett, Ronald W.; Gallop, Mark A.

doi:10.1124/jpet.104.067934

Cited by 148 publications

(126 citation statements)

References 40 publications

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“…The expression of MCT1 in the intestine can be exploited to improve the bioavailability of substrate drugs. For instance, XP13512, a prodrug of gabapentin, was specifically designed as MCT1 substrate to improve the bioavailability of the pharmacologically active metabolite 86. Similarly, the prodrug arbaclofen placarbil (XP19986) has improved the bioavailability of the active drug R‐baclofen due to better absorption from the colon, which was found to rely on MCT1‐mediated transport 87…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Fisel

Schaeffeler

Schwab

2018

Clinical Translational Sci

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The solute carrier (SLC) SLC16 gene family comprises 14 members and encodes for monocarboxylate transporters (MCTs), which mediate the absorption and distribution of monocarboxylic compounds across plasma membranes. As the knowledge about their physiological function, activity, and regulation increases, their involvement and contribution to cancer and other diseases become increasingly evident. Moreover, promising opportunities for therapeutic interventions by directly targeting their endogenous functions or by exploiting their ability to deliver drugs to specific organ sites emerge.

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Section: Therapeutic Approachesmentioning

confidence: 99%

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Fisel

Schaeffeler

Schwab

2018

Clinical Translational Sci

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“…Drug targeting using CMT requires either mimicking the natural small molecule ligand or conjugation to the endogenous substrate of the carrier protein. This can be successful for small molecule CNS drugs, such as gabapentin and L-dopa, both of which are delivered primarily through the cerebrovascular large neutral amino acid transporter (LAT1) carrier system [102,103]. However, neither approach is conducive to large molecule transport required for brain uptake of antibody therapeutics.…”

Section: Endogenous Transport Systems As a Means To Enhance Antibody mentioning

confidence: 99%

Developing Therapeutic Antibodies for Neurodegenerative Disease

Yu¹,

Watts²

2013

Neurotherapeutics

170

171

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The central nervous system has been considered off-limits to antibody therapeutics. However, recent advances in preclinical and clinical drug development suggest that antibodies can cross the blood-brain barrier in limited quantities and act centrally to mediate their effects. In particular, immunotherapy for Alzheimer's disease has shown that targeting beta amyloid with antibodies can reduce pathology in both mouse models and the human brain, with strong evidence supporting a central mechanism of action. These findings have fueled substantial efforts to raise antibodies against other central nervous system targets, particularly neurodegenerative targets, such as tau, beta-secretase, and alpha-synuclein. Nevertheless, it is also apparent that antibody penetration across the blood-brain barrier is limited, with an estimated 0.1-0.2 % of circulating antibodies found in brain at steady-state concentrations. Thus, technologies designed to improve antibody uptake in brain are receiving increased attention and are likely going to represent the future of antibody therapy for neurologic diseases, if proven safe and effective. Herein we review briefly the progress and limitations of traditional antibody drug development for neurodegenerative diseases, with a focus on passive immunotherapy. We also take a more in-depth look at new technologies for improved delivery of antibodies to the brain.

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“…its bioavailability ranges from 30-60% of the dose (300 mg) used to treat neuropathic pain [22]. probably due to its charged amine group; however, its prodrug XP13512, combines the properties required for recognition by both high-capacity transporters, allowing for its direct uptake across human embryonic kidney (HEK) cells [22]. The transcellular flux of XP13512…”

Section: Improving Active Transportmentioning

confidence: 99%

Current and evolving approaches for improving the oral permeability of BCS Class III or analogous molecules

Dave

Gupta

et al. 2016

Drug Development and Industrial Pharmacy

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The Biopharmaceutics Classification System (BCS) classifies pharmaceutical compounds based on their aqueous solubility and intestinal permeability. The BCS Class III compounds are hydrophilic molecules (high aqueous solubility) with low permeability across the biological membranes. While these compounds are pharmacologically effective, poor absorption due to low permeability becomes the rate-limiting step in achieving adequate bioavailability. Several approaches have been explored and utilized for improving the permeability profiles of these compounds. The approaches include traditional methods such as prodrugs, permeation enhancers, ion-pairing, etc., as well as relatively modern approaches such as nanoencapsulation and nanosizing. The most recent approaches include a combination/hybridization of one or more traditional approaches to improve drug permeability. While some of these approaches have been extremely successful, i.e. drug products utilizing the approach have progressed through the USFDA approval for marketing; others require further investigation to be applicable. This article discusses the commonly studied approaches for improving the permeability of BCS Class III compounds. AbstractThe Biopharmaceutics Classification System (BCS) classifies pharmaceutical compounds based on their aqueous solubility and intestinal permeability. The BCS Class III compounds are hydrophilic molecules (high aqueous solubility) with low permeability across the biological membranes. While these compounds are pharmacologically effective, poor absorption due to low permeability becomes the rate-limiting step in achieving adequate bioavailability.Several approaches have been explored and utilized for improving the permeability profiles of these compounds. The approaches include traditional methods such as prodrugs, permeation enhancers, ion-pairing, etc., as well as relatively modern approaches such as nanoencapsulation and nanosizing. The most recent approaches include a combination/ hybridization of one or more traditional approaches to improve drug permeability. While some of these approaches have been extremely successful, i.e. drug products utilizing the approach have progressed through the USFDA approval for marketing; others require further investigation to be applicable. This article discusses the commonly studied approaches for improving the permeability of BCS Class III compounds.

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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

Cited by 148 publications

References 40 publications

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Developing Therapeutic Antibodies for Neurodegenerative Disease

Current and evolving approaches for improving the oral permeability of BCS Class III or analogous molecules

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