Vitamin C and 6-amino-vitamin C conjugates of diclofenac: synthesis and evaluation

Dalpiaz, Alessandro; Pavan, Barbara; Scaglianti, Martina; Vitali, Federica; Bortolotti, Fabrizio; Biondi, Carla; Scatturin, Angelo; Manfredini, Stefano

doi:10.1016/j.ijpharm.2004.07.054

Cited by 20 publications

(18 citation statements)

References 17 publications

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“…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

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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.

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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

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“…There are some literature reports on the substrate specificity of the AsA transporter using biological tissues or cells. [28][29][30][31][32] As most AsA exists as a monovalent anion at physiological pH and SVCT has a high affinity for the ionic form, it has been suggested that the ionic interactions between SVCT and its substrates are the predominant driving forces for the binding of SVCT. 31,32) Studies by Rumsey et al 33) demonstrated that one of the structural requisites of AsA and its analogs for transport in cells is an S-absolute configuration at the C-4 position in a five-membered reduced ring with no substitution on the C-2 and C-3 positions, and that 6-deoxy-6-halogeno-Lascorbic acid is an effective compound for inhibiting AsA uptake.…”

Section: Resultsmentioning

confidence: 99%

5-O-(4-[125I]Iodobenzyl)-L-ascorbic Acid: Electrophilic Radioiodination and Biodistribution in Mice

Kim

Kino

Kato

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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As a part of our efforts to develop potential imaging agents for ascorbate bioactivity, 5-O-(4-[125 I] iodobenzyl)-L-ascorbic acid ([ 125 I]1) was prepared through a two-step sequence which involved radioiododestannylation of a protected tributylstannyl precursor 6, followed by hydrolysis in acidic methanol of the protecting groups in 61% overall radiochemical yield, with a radiochemical purity of over 98% and a specific activity of more than 15.4 GBq/μmol. Tissue distribution of [ 125 I]1 in tumor-bearing mice showed signs of distribution profiles similar to the reported results for 6-deoxy-6-[18 F]fluoro-L-ascorbic (6-18 FAsA) acid and 6-deoxy-6-[131 I]iodo-L-ascorbic acid (6-131 IAsA) but with notable differences in the adrenal glands, in which considerably lower uptake of radioactivity and rapid clearance with time were observed. Pretreatment of mice with a known inhibitor of ascorbate transport, sulfinpyrazone, did not produce any significant change in the adrenal uptake of radioactivity after injection of [ 125 I]1 compared to the control, suggesting that uptake in the adrenal glands is independent of the sodium-dependent vitamin C transporter 2 transport mechanism. Introduction of a bulky substituent at C-5 on AsA, such as an iodobenzyloxy group, may not be suitable for the design of analogs that may still be able to maintain characteristic distribution properties in vivo seen with AsA itself.

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“…Hence higher ocular bioavailability of therapeutic agents can be achieved. In addition to peptide (PepT1) [87, 90], amino acid (LAT1, LAT2, B(0,+)) [84, 91] and monocarboxylic acid (MCT) [92, 93] transporters, recently various vitamin transporters such biotin [94] and ascorbic acid (SVCT2) [95-98] have been utilized for the delivery of various ocular prodrugs.…”

Section: 2 Transporter Targeted Prodrug Approachmentioning

confidence: 99%

Prodrug Strategies in Ocular Drug Delivery

Barot

Bagui²,

Gokulgandhi³

et al. 2012

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Poor bioavailability of topically instilled drug is the major concern in the field of ocular drug delivery. Efflux transporters, static and dynamic ocular barriers often possess rate limiting factors for ocular drug therapy. Different formulation strategies like suspension, ointment, gels, nanoparticles, implants, dendrimers and liposomes have been employed in order to improve drug permeation and retention by evading rate limiting factors at the site of absorption. Chemical modification such as prodrug targeting various nutrient transporters (amino acids, peptide and vitamin) has evolved a great deal ofintereSt to improve ocular drug delivery. In this review, we have discussed various prodrug strategies which have been widely applied for enhancing therapeutic efficacy of ophthalmic drugs. The purpose of this review is to provide an update on the utilization of prodrug concept in ocular drug delivery. In addition, this review will highlight ongoing academic and industrial research and development in terms of ocular prodrug design and delivery.

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Vitamin C and 6-amino-vitamin C conjugates of diclofenac: synthesis and evaluation

Cited by 20 publications

References 17 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

5-O-(4-[125I]Iodobenzyl)-L-ascorbic Acid: Electrophilic Radioiodination and Biodistribution in Mice

Prodrug Strategies in Ocular Drug Delivery

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