ArticleInternational journal of pharmaceutics2011
Targeting SVCT for enhanced drug absorption: synthesis and in vitro evaluation of a novel vitamin C conjugated prodrug of saquinavir.
Article in International journal of pharmaceutics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Vitamin C Conjugates in Biomedicine: A Comprehensive Exploration with Drugs, Polymers, Proteins, and Peptides.Mini reviews in medicinal chemistry · 2026Review
- Enhancement of saquinavir absorption and accumulation through the formation of solid drug nanoparticles.BMC pharmacology & toxicology · 2018Article
- Conjugation to Ascorbic Acid Enhances Brain Availability of Losartan Carboxylic Acid and Protects Against Parkinsonism in Rats.The AAPS journal · 2018Article
- Circumvention of P-gp and MRP2 mediated efflux of lopinavir by a histidine based dipeptide prodrug.International journal of pharmaceutics · 2016Article
- Prodrug approach to improve absorption of prednisolone.International journal of pharmaceutics · 2015Article
- Functional characterization and molecular identification of vitamin C transporter (SVCT2) in human corneal epithelial (HCEC) and retinal pigment epithelial (D407) cells.Current eye research · 2015Article
- Dipeptide prodrug approach to evade efflux pumps and CYP3A4 metabolism of lopinavir.International journal of pharmaceutics · 2014Article
- Molecular expression and functional activity of vitamin C specific transport system (SVCT2) in human breast cancer cells.International journal of pharmaceutics · 2014Article
- Amino Acid Prodrugs: An Approach to Improve the Absorption of HIV-1 Protease Inhibitor, Lopinavir.Pharmaceuticals (Basel, Switzerland) · 2014Article
- Expression, purification and low-resolution structure of human vitamin C transporter SVCT1 (SLC23A1).PloS one · 2013Article
- Sodium dependent multivitamin transporter (SMVT): a potential target for drug delivery.Current drug targets · 2012Review
- Binding of novel fullerene inhibitors to HIV-1 protease: insight through molecular dynamics and molecular mechanics Poisson-Boltzmann surface area calculations.Journal of computer-aided molecular design · 2011Article
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Authors and funding
7 authors.
Funding
Abstract
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 efflux pump 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 [(3)H]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 [(14)C]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 5mM 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 5mM 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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