Transport of butyryl-<scp>l</scp>-carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB<sup>0,+</sup>

Srinivas, Sonne R.; Prasad, Puttur D.; Umapathy, Nagavedi S.; Ganapathy, Vadivel; Shekhawat, Prem

doi:10.1152/ajpgi.00233.2007

Cited by 60 publications

(57 citation statements)

References 63 publications

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“…141 Long-chain fatty acids are obligated to be processed this way, but SCFAs can also use this pathway too. 142 Thus, as Srinivas et al 135 reported, butyryl- l -carnitine can act as a prodrug for delivering butyrate into cells in vivo , and our own studies (article in preparation) found that butyryl- l -carnitines, PMX ™ 550B and PMX 550D (Fig. 6), are more potent HDACi than butyrate itself.…”

Section: Butyryl-l-carnitine Esterssupporting

confidence: 55%

“…Unlike the sugar transporters, which highly discriminate against synthetically modified sugars, the acylcarnitine transporters appear to tolerate a range of acyl-substrate variations 118 that can traverse both the plasma 118,135,140 and blood–brain barriers. 133,134 PMX 550B and PMX 550D are strong butyrate HDACi, and their potential for oral delivery and mitigation of short-half life may lead to more effective epigenetic therapeutics for treating the thalassemias, sickle-cell disease, neurological disorders, and cancer.…”

Section: Discussionmentioning

confidence: 99%

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Butyrate Histone Deacetylase Inhibitors

Steliou

Boosalis

Perrine

et al. 2012

BioResearch Open Access

152

107

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In addition to being a part of the metabolic fatty acid fuel cycle, butyrate is also capable of inducing growth arrest in a variety of normal cell types and senescence-like phenotypes in gynecological cancer cells, inhibiting DNA synthesis and cell growth in colonic tumor cell lines, suppressing hTERT mRNA expression and telomerase activity in human prostate cancer cells, and inducing stem cell differentiation and apoptosis by DNA fragmentation. It regulates gene expression by inhibiting histone deacetylases (HDACs), enhances memory recovery and formation in mice, stimulates neurogenesis in the ischemic brain, promotes osteoblast formation, selectively blocks cell replication in transformed cells (compared to healthy cells), and can prevent and treat diet-induced obesity and insulin resistance in mouse models of obesity, as well as stimulate fetal hemoglobin expression in individuals with hematologic diseases such as the thalassemias and sickle-cell disease, in addition to a multitude of other biochemical effects in vivo. However, efforts to exploit the potential of butyrate in the clinical treatment of cancer and other medical disorders are thwarted by its poor pharmacological properties (short half-life and first-pass hepatic clearance) and the multigram doses needed to achieve therapeutic concentrations in vivo. Herein, we review some of the methods used to overcome these difficulties with an emphasis on HDAC inhibition.

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Section: Butyryl-l-carnitine Esterssupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Butyrate Histone Deacetylase Inhibitors

Steliou

Boosalis

Perrine

et al. 2012

BioResearch Open Access

152

107

View full text Add to dashboard Cite

show abstract

“…It has poor pharmacokinetic properties (short half-life and first-pass hepatic clearance) and multigram doses are needed to achieve therapeutic concentrations in vivo Moos et al, 2016]. However, when butyrate and other SCFAs, including lipoic acid, present as acylcarnitine esters [Knoop, 1904;Bieber et al, 1982;Bieber, 1988;Nałezcz et al, 2004;Houten and Wanders, 2010], the body's natural carnitine-acylcarnitine transport machinery actively delivers the ester into cells, an effect that substantially increases the bioavailability of the corresponding acyl-CoA [Chenault et al, 1988;Billhardt et al, 1989;Srinivas et al, 2007;Gong et al, 2008;Piermatti et al, 2008;Rosca et al, 2009;Steliou et al, 2009Steliou et al, , 2012Parameshwaran et al, 2010Parameshwaran et al, , 2012.…”

Section: Apoptotic Priming In Mitochondriamentioning

confidence: 99%

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

Irwin

Moos

Faller

et al. 2016

Drug Development Research

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Preclinical Research In this review, we discuss epigenetic-driven methods for treating neurodegenerative disorders associated with mitochondrial dysfunction, focusing on carnitinoid antioxidant-histone deacetylase inhibitors that show an ability to reinvigorate synaptic plasticity and protect against neuromotor decline in vivo. Aging remains a major risk factor in patients who progress to dementia, a clinical syndrome typified by decreased mental capacity, including impairments in memory, language skills, and executive function. Energy metabolism and mitochondrial dysfunction are viewed as determinants in the aging process that may afford therapeutic targets for a host of disease conditions, the brain being primary in such thinking. Mitochondrial dysfunction is a core feature in the pathophysiology of both Alzheimer and Parkinson diseases and rare mitochondrial diseases. The potential of new therapies in this area extends to glaucoma and other ophthalmic disorders, migraine, Creutzfeldt-Jakob disease, post-traumatic stress disorder, systemic exertion intolerance disease, and chemotherapy-induced cognitive impairment. An emerging and hopefully more promising approach to addressing these hard-to-treat diseases leverages their sensitivity to activation of master regulators of antioxidant and cytoprotective genes, antioxidant response elements, and mitophagy. Drug Dev Res 77 : 109-123, 2016. © 2016 Wiley Periodicals, Inc.

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“…Butyrate, a bacterial fermentation product, is beneficial for prevention/treatment of ulcerative colitis. 36 BC inhibited ATB (0, þ)-mediated Gly transport in mammalian cells, and BC induced Na þ -dependent inward currents under voltage-clamp conditions. BC inhibited OCTN2-mediated carnitine uptake, and transport of BC via OCTN2 was electrogenic, as evidenced from BC-induced inward currents.…”

Section: Ketoprofenmentioning

confidence: 87%

A Minireview: Usefulness of Transporter-Targeted Prodrugs in Enhancing Membrane Permeability

Murakami

2016

Journal of Pharmaceutical Sciences

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Orally administered drugs are categorized into 4 classes depending on the solubility and permeability in a Biopharmaceutics Classification System. Prodrug derivatization is one of feasible approaches in modifying the physicochemical properties such as low solubility and low permeability without changing the in vivo pharmacological action of the parent drug. In this article, prodrug-targeted solute carrier (SLC) transporters were searched randomly by PubMed. Collected SLC transporters are amino acid transporter 1, bile acid transporter, carnitine transporter 2, glucose transporter 1, peptide transporter 1, vitamin C transporter 1, and multivitamin transporter. The usefulness of transporter-targeted prodrugs was evaluated in terms of membrane permeability, stability under acidic condition, and conversion to the parent drug. Among prodrugs collected, peptide transporter-targeted prodrugs exhibited the highest number, and some prodrugs such as valaciclovir and valganciclovir are clinically available. ATP-binding cassette efflux transporter, P-glycoprotein (P-gp), reduces the intestinal absorption of lipophilic P-gp substrate drugs, and SLC transporter-targeted prodrugs of P-gp substrate drugs circumvented the P-gp-mediated efflux transport. Thus, SLC transporter-targeted prodrug derivatization seems to be feasible approach to increase the oral bioavailability by overcoming various unwanted physicochemical properties of orally administered drugs, although the effect of food on prodrug absorption should be taken into consideration.

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Transport of butyryl-l-carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB^0,+

Abstract: Srinivas SR, Prasad PD, Umapathy NS, Ganapathy V, Shekhawat PS. Transport of butyryl-L-carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB 0,ϩ .

Cited by 60 publications

References 63 publications

Butyrate Histone Deacetylase Inhibitors

Butyrate Histone Deacetylase Inhibitors

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

A Minireview: Usefulness of Transporter-Targeted Prodrugs in Enhancing Membrane Permeability

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Transport of butyryl-l-carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB0,+

Abstract: Srinivas SR, Prasad PD, Umapathy NS, Ganapathy V, Shekhawat PS. Transport of butyryl-L-carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB 0,ϩ .

Cited by 60 publications

References 63 publications

Butyrate Histone Deacetylase Inhibitors

Butyrate Histone Deacetylase Inhibitors

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

A Minireview: Usefulness of Transporter-Targeted Prodrugs in Enhancing Membrane Permeability

Contact Info

Product

Resources

About

Transport of butyryl-l-carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB^0,+