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Surendran, Narayanan; Covitz, Kuang Ming Y.; Han, Hyo Kyung; Sadée, Wolfgang; Oh, Doo Man; Amidon, Gordon L.; Williamson, Rufus M.; Bigge, Christopher F.; Stewart, Barbra H.

doi:10.1023/a:1018821718340

Cited by 20 publications

(3 citation statements)

References 11 publications

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“…PEPT1 has broad substrate specificity and is expressed in the GI tract [25,26]. This transporter can transport dipeptides, tripeptides, amino acid monoester prodrugs and β-lactam antibiotics [11,27,28,29,30,31,32,33]. Yang and coworkers demonstrated that the importance of PEPT1 transporter for the oral absorption of valacyclovir in PEPT1 knockout mice [34].…”

Section: Introductionmentioning

confidence: 99%

The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable Nucleoside Analogs

2014

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Dipeptide monoester prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their parent drugs. Floxuridine prodrug was more enzymatically stable than floxuridine and the degradation from prodrug to parent drug works as the rate-limiting step. On the other hand, gemcitabine prodrug was less enzymatically stable than gemcitabine. Those dipeptide monoester prodrugs exhibited 2.4- to 48.7-fold higher uptake than their parent drugs in Caco-2, Panc-1, and AsPC-1 cells. Floxuridine and gemcitabine prodrugs showed superior permeability in mouse jejunum to their parent drugs and exhibited the higher drug concentration in plasma after in situ mouse perfusion. Cell proliferation assays in ductal pancreatic cancer cells, AsPC-1 and Panc-1, indicated that dipeptide prodrugs of floxuridine and gemcitabine were more potent than their parent drugs. The enhanced potency of nucleoside analogs was attributed to their improved membrane permeability. The prodrug forms of 5′-l-phenylalanyl-l-tyrosyl-floxuridine and 5′-l-phenylalanyl-l-tyrosyl-gemcitabine appeared in mouse plasma after the permeation of intestinal membrane and the first-pass effect, suggesting their potential for the development of oral dosage form for anti-cancer agents.

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Section: Introductionmentioning

confidence: 99%

The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable Nucleoside Analogs

2014

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“…Various dipeptides and peptidomimetics have been tested to characterize the hPEPT1 transporter and improve its affinity, 6,17−19,22,35−37 and mono amino acid ester prodrugs have been evaluated as hPEPT1 substrates. 3,13,14 Based on those reports, six amino acids were chosen to be N-terminal amino acids of the dipeptide.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Cancer Cell Growth Inhibition by Dipeptide Prodrugs of Floxuridine: Increased Transporter Affinity and Metabolic Stability

2008

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Dipeptide monoester prodrugs of floxuridine were synthesized, and their chemical stability in buffers, resistance to glycosidic bond metabolism, affinity for PEPT1, enzymatic activation and permeability in cancer cells were determined and compared to those of mono amino acid monoester floxuridine prodrugs. Prodrugs containing glycyl moieties were the least stable in pH 7.4 buffer (t1/2 < 100 min). The activation of all floxuridine prodrugs was 2- to 30-fold faster in cell homogenates than their hydrolysis in buffer, suggesting enzymatic action. The enzymatic activation of dipeptide monoester prodrugs containing aromatic promoieties in cell homogenates was 5- to 20-fold slower than that of other dipeptide and most mono amino acid monoester prodrugs (t1/2 ∼ 40 to 100 min). All prodrugs exhibited enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase compared to parent floxuridine. In general, the 5′-O-dipeptide monoester floxuridine prodrugs exhibited higher affinity for PEPT1 than the corresponding 5′-O-mono amino acid ester prodrugs. The permeability of dipeptide monoester prodrugs across Caco-2 and Capan-2 monolayers was 2- to 4-fold higher than the corresponding mono amino acid ester prodrug. Cell proliferation assays in AsPC-1 and Capan-2 pancreatic ductal cell lines indicated that the dipeptide monoester prodrugs were equally as potent as mono amino acid prodrugs. The transport and enzymatic profiles of 5′-l-phenylalanyl-l-tyrosyl-floxuridine, 5′-l-phenylalanyl-l-glycyl-floxuridine, and 5′-l-isoleucyl-l-glycyl-floxuridine suggest their potential for increased oral uptake, delayed enzymatic bioconversion and enhanced resistance to metabolism to 5-fluorouracil, as well as enhanced uptake and cytotoxic activity in cancer cells, attributes that would facilitate prolonged systemic circulation for enhanced therapeutic action.

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“…Amino acid ester prodrugs of floxuridine and the antiviral agent acyclovir have been shown to be substrates of the PEPT1 transporter [ 14 , 15 ]. PEPT1 has broad substrate specificity for dipeptides, tripeptides, and β-lactam antibiotics [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Improved oral bioavailability of the valyl ester prodrug of acyclovir has been attributed to the presence of oligopeptide transporters [ 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Enhanced Absorption and Growth Inhibition with Amino Acid Monoester Prodrugs of Floxuridine by Targeting hPEPT1 Transporters

et al. 2008

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A series of amino acid monoester prodrugs of floxuridine was synthesized and evaluated for the improvement of oral bioavailability and the feasibility of target drug delivery via oligopeptide transporters. All floxuridine 5′-amino acid monoester prodrugs exhibited PEPT1 affinity, with inhibition coefficients of Gly-Sar uptake (IC50) ranging from 0.7 – 2.3 mM in Caco-2 and 2.0 – 4.8 mM in AsPC-1 cells, while that of floxuridine was 7.3 mM and 6.3 mM, respectively. Caco-2 membrane permeabilities of floxuridine prodrugs (1.01 – 5.31 x 10-6 cm/sec) and floxuridine (0.48 x 10-6 cm/sec) were much higher than that of 5-FU (0.038 x 10-6 cm/sec). MDCK cells stably transfected with the human oligopeptide transporter PEPT1 (MDCK/hPEPT1) exhibited enhanced cell growth inhibition in the presence of the prodrugs. This prodrug strategy offers great potential, not only for increased drug absorption but also for improved tumor selectivity and drug efficacy.

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Cited by 20 publications

References 11 publications

The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable Nucleoside Analogs

The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable Nucleoside Analogs

Enhanced Cancer Cell Growth Inhibition by Dipeptide Prodrugs of Floxuridine: Increased Transporter Affinity and Metabolic Stability

Enhanced Absorption and Growth Inhibition with Amino Acid Monoester Prodrugs of Floxuridine by Targeting hPEPT1 Transporters

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