Transporter-Mediated Effects of Diclofenamic Acid and its Ascorbyl Pro-Drug in the in Vivo Neurotropic Activity of Ascorbyl Nipecotic Acid Conjugate

Dalpiaz, Alessandro; Pavan, Barbara; Scaglianti, Martina; Vitali, Federica; Bortolotti, Fabrizio; Biondi, Carla; Scatturin, Angelo; Tanganelli, Sergio; Ferraro, Luca; Prasad, Puttur D.; Manfredini, Stefano

doi:10.1002/jps.10532

Cited by 23 publications

(25 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, AA and analogs may possess antiviral activity (Harakeh et al, 1990; Furuya et al, 2008) and inhibit P-gp expression (El-Masry and Abou-Donia, 2003). In addition, previous studies demonstrated that AA conjugated prodrug of nipecotic acid was recognized by SVCT2 and the prodrug derivation facilitated the drug accumulation and the drug entry to the mouse brain (Manfredini et al, 2002; Dalpiaz et al, 2004). Finally, SVCT transporters responsible for AA uptake are abundantly available in various tissues.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting SVCT for enhanced drug absorption: Synthesis and in vitro evaluation of a novel vitamin C conjugated prodrug of saquinavir

Luo

Wang

Patel

et al. 2011

International Journal of Pharmaceutics

View full text Add to dashboard Cite

In order to improve oral absorption, a novel prodrug of saquinavir (Saq), ascorbyl-succinic-saquinavir (AA-Su-Saq) targeting sodium dependent vitamin C transporter (SVCT) was synthesized and evaluated. Aqueous solubility, stability and cytotoxicity were determined. Affinity of AA-Su-Saq towards effluxpump P-glycoprotein (P-gp) and recognition of AA-Su-Saq by SVCT were studied. Transepithelial permeability across polarized MDCK-MDR1 and Caco-2 cells were determined. Metabolic stability of AA-Su-Saq in rat liver microsomes was investigated. AA-Su-Saq appears to be fairly stable in both DPBS and Caco-2 cells with half lives of 9.65 and 5.73 h, respectively. Uptake of [3H]Saquinavir accelerated by 2.7 and 1.9 fold in the presence of 50 μM Saq and AA-Su-Saq in MDCK-MDR1 cells. Cellular accumulation of [14C]AA diminished by about 50–70% relative to control in the presence of 200 μM AA-Su-Saq in MDCK-MDR1 and Caco-2 cells. Uptake of AA-Su-Saq was lowered by 27% and 34% in the presence of 5 mM AA in MDCK-MDR1 and Caco-2 cells, respectively. Absorptive permeability of AA-Su-Saq was elevated about 4-5 fold and efflux index reduced by about 13-15 fold across the polarized MDCK-MDR1 and Caco-2 cells. Absorptive permeability of AA-Su-Saq decreased 44% in the presence of 5 mM AA across MDCK-MDR1 cells. AA-Su-Saq was devoid of cytotoxicity over the concentration range studied. AA-Su-Saq significantly enhanced the metabolic stability but lowered the affinity towards CYP3A4. In conclusion, prodrug modification of Saq through conjugation to AA via a linker significantly raised the absorptive permeability and metabolic stability. Such modification also caused significant evading of P-gp mediated efflux and CYP3A4 mediated metabolism. SVCT targeted prodrug approach can be an attractive strategy to enhance the oral absorption and systemic bioavailability of anti-HIV protease inhibitors.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Recently, SVCT2-mediated delivery of neurotropic agents to the central nervous system (CNS) was reported (Manfredini et al, 2002, 2004; Dalpiaz et al, 2004, 2005). Several AA or AA derivative (BrAA, AA-NH) conjugated prodrugs of nipecotic (Nipec), kynurenic (Kynur) and diclofenamic (Diclo) acids were evaluated.…”

Section: Introductionmentioning

confidence: 99%

Targeting SVCT for enhanced drug absorption: Synthesis and in vitro evaluation of a novel vitamin C conjugated prodrug of saquinavir

Luo

Wang

Patel

et al. 2011

International Journal of Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…This observation coincides with the previous ndings that C6-OH derived AA esters usually exhibit higher affinity against SVCTs over the endogenous AA. 22,23 Thus, it is not necessary to be worried about the AA inuence on SVCT imaging by competition with RB-A-Vc binding. Moreover, the high affinity leads to a fast binding and slow dissociation of RB-A-Vc/SVCT complexes, greatly facilitating the uorescence imaging of the complexes in a relatively stable state.…”

Section: Specicity Of Rb-a-vc/svct Bindingmentioning

confidence: 99%

A fluorophore-conjugated ascorbic acid functions for the visualization of sodium vitamin C transporters in living cells

Yin

Zhang

et al. 2015

Anal. Methods

View full text Add to dashboard Cite

Human beings do not produce ascorbic acid (AA) and acquire AA through the sodium vitamin C transporters (SVCTs). Changes in the expression or function of SVCT proteins may be associated with human diseases. In this regard, imaging of SVCTs in living cells is important. However, the options for live-cell labelling of SVCTs were very limited. In this work, we synthesized a new small-molecule fluorescent probe RB-A-Vc, and demonstrated its application in selectively visualizing SVCTs in living cells. This probe features visible excitation and emission profiles, can easily enter into membranes, has high selectivity for SVCTs, and can monitor up-regulation or down-regulation of SVCT expression in living cells. We emphasize that this smallmolecule probe is suitable for subcellular localization of SVCTs in living cells. This study provides a useful tool for simultaneously monitoring the level and distribution of intracellular SVCTs, which is probably more useful for evaluating the changes induced by external stimulations. We propose that this probe for SVCT imaging and the corresponding method could be applied to other cell lines, tissues, and species.

show abstract

“…Although numerous carbon‐6‐modified ascorbate derivatives have been prepared (Cousins et al ., 1977; Raic‐Malic et al ., 1999; Manfredini et al . 2002; Dalpiaz et al . 2004; 2005), affinity ligands for the SVCT transporters have not been reported.…”

Section: Pharmacologymentioning

confidence: 99%

The SLC23 family of ascorbate transporters: ensuring that you get and keep your daily dose of vitamin C

May

2011

British J Pharmacology

View full text Add to dashboard Cite

The ascorbate transporters SVCT1 and SVCT2 are crucial for maintaining intracellular ascorbate concentrations in most cell types. Although the two transporter isoforms are highly homologous, they have different physiologic functions. The SVCT1 is located primarily in epithelial cells and has its greatest effect in reabsorbing ascorbate in the renal tubules. The SVCT2 is located in most non-epithelial tissues, with the highest expression in brain and neuroendocrine tissues. These transporters are hydrophobic membrane proteins that have a high affinity and are highly selective for ascorbate. Their ability to concentrate ascorbate inside cells is driven by the sodium gradient across the plasma membrane as generated by Na+/K+ ATPase. They can concentrate ascorbate 20 to 60-fold over plasma ascorbate concentrations. Ascorbate transport on these proteins is regulated at the transcriptional, translational and post-translational levels. Available studies show that transporter function is acutely regulated by protein kinases A and C, whereas transporter expression is increased by low intracellular ascorbate and associated oxidative stress. The knockout of the SVCT2 in mice is lethal on day 1 of life, and almost half of SVCT1 knockout mice do not survive to weaning. These findings confirm the importance both of cellular ascorbate and of the two transport proteins as key to maintaining intracellular ascorbate. LINKED ARTICLESThis article is part of a themed section on Transporters. To view the other articles in this section visit http://dx

show abstract

Transporter-Mediated Effects of Diclofenamic Acid and its Ascorbyl Pro-Drug in the in Vivo Neurotropic Activity of Ascorbyl Nipecotic Acid Conjugate

Cited by 23 publications

References 26 publications

Targeting SVCT for enhanced drug absorption: Synthesis and in vitro evaluation of a novel vitamin C conjugated prodrug of saquinavir

Targeting SVCT for enhanced drug absorption: Synthesis and in vitro evaluation of a novel vitamin C conjugated prodrug of saquinavir

A fluorophore-conjugated ascorbic acid functions for the visualization of sodium vitamin C transporters in living cells

The SLC23 family of ascorbate transporters: ensuring that you get and keep your daily dose of vitamin C

Contact Info

Product

Resources

About