Amino Acid Ester Prodrugs of Acyclovir

Beauchamp, Lilia M.; Orr, G F; Miranda, Paulo de; Bumette, T.; Krenitsky, Thomas A.

doi:10.1177/095632029200300305

Cited by 202 publications

(143 citation statements)

References 25 publications

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“…The aspartyl prodrugs were more chemically stable potentially due to the negatively charged side chain that may hinder hydroxide ion catalysis of the ester bond. The greater stability of the prodrugs at pH 6.0 can be attributed to a lower hydroxide ion concentration and is consistent with previous findings with acyl floxuridine esters (24) and with valacyclovir (25,26). These results also suggest that degradation of the prodrugs is not substantial (<20% for monoesters) over the time course of the uptake experiments conducted at pH 6.0 to provide the proton gradient necessary for PEPT1-mediated uptake.…”

Section: Discussionsupporting

confidence: 79%

Targeted delivery to PEPT1-overexpressing cells: Acidic, basic, and secondary floxuridine amino acid ester prodrugs

Landowski

Vig

Song

et al. 2005

Molecular Cancer Therapeutics

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Floxuridine is a clinically proven anticancer agent in the treatment of metastatic colon carcinomas and hepatic metastases. However, prodrug strategies may be necessary to improve its physiochemical properties and selectivity and to reduce undesirable toxicity effects. Previous studies with amino acid ester prodrugs of nucleoside drugs targeted to the PEPT1 transporter coupled with recent findings of the functional expression of the PEPT1 oligopeptide transporter in pancreatic adenocarcinoma cell lines suggest the potential of PEPT1 as therapeutic targets for cancer treatment. In this report, we show the feasibility of achieving enhanced transport and selective antiproliferative action of amino acid ester prodrugs of floxuridine in cell systems overexpressing PEPT1. All prodrugs exhibited affinity for PEPT1 (IC 50 , 1.1 -2.3 mmol/L). However, only the prolyl and lysyl prodrugs exhibited enhanced uptake (2-to 8-fold) with HeLa/PEPT1 cells compared with HeLa cells, suggesting that the aspartyl prodrugs are PEPT1 inhibitors. The selective growth inhibition of Madine-Darby canine kidney (MDCK)/PEPT1 cells over MDCK cells by the prodrugs was consistent with the extent of their PEPT1-mediated transport. All ester prodrugs hydrolyzed to floxuridine fastest in Caco-2 cell and MDCK homogenates and slower in human plasma and were most chemically stable in pH 6.0 buffer. Prolyl and lysyl prodrugs were relatively less stable compared with aspartyl prodrugs in buffers and in cell homogenates. The results suggest that optimal design for targeted delivery would be possible by combining both stability and transport characteristics afforded by the promoiety. [Mol Cancer Ther 2005;4(4):659 -67]

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Section: Discussionsupporting

confidence: 79%

Targeted delivery to PEPT1-overexpressing cells: Acidic, basic, and secondary floxuridine amino acid ester prodrugs

Landowski

Vig

Song

et al. 2005

Molecular Cancer Therapeutics

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“…For example, oligopeptide transporters are responsible for the active absorption of -lactam antibiotics, the ACE inhibitor enalapril, valaciclovir and valganciclovir. The BA of valaciclovir was 5 times higher than that of aciclovir itself due to transport by the intestinal oligopepetide transporter PEPT1 (Beauchamp et al 1992;Swaan & Tukker 1997;Han et al 1998).…”

Section: The Bcs In the Pharmaceutical Development Phasementioning

confidence: 99%

The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension

Lennernäs

Abrahamsson

2005

Journal of Pharmacy and Pharmacology

184

119

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Bioavailability (BA) and bioequivalence (BE) play a central role in pharmaceutical product development and BE studies are presently being conducted for New Drug Applications (NDAs) of new compounds, in supplementary NDAs for new medical indications and product line extensions, in Abbreviated New Drug Applications (ANDAs) of generic products and in applications for scale-up and post-approval changes. The Biopharmaceutics Classification System (BCS) has been developed to provide a scientific approach for classifying drug compounds based on solubility as related to dose and intestinal permeability in combination with the dissolution properties of the oral immediaterelease (IR) dosage form. The aim of the BCS is to provide a regulatory tool for replacing certain BE studies by accurate in-vitro dissolution tests. The aim of this review is to present the status of the BCS and discuss its future application in pharmaceutical product development. The future application of the BCS is most likely increasingly important when the present framework gains increased recognition, which will probably be the case if the BCS borders for certain class II and III drugs are extended. The future revision of the BCS guidelines by the regulatory agencies in communication with academic and industrial scientists is exciting and will hopefully result in an increased applicability in drug development. Finally, we emphasize the great use of the BCS as a simple tool in early drug development to determine the rate-limiting step in the oral absorption process, which has facilitated the information between different experts involved in the overall drug development process. This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in drug molecules with a sufficiently high permeability, solubility and dissolution rate, and that will automatically increase the importance of the BCS as a regulatory tool over time.

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“…Therefore, to reduce the rapid deamination during intestinal absorption, the N4-amino group of the cytosine ring was masked with L-valine in this study. Since previous studies have reported that L-valine may have the optimal combination of chain length and branching at the beta carbon of the amino acid for the intestinal absorption of peptidomimetic drugs (Beauchamp et al 1992;Han et al 1998;Sugawara et al 2000), L-valine was selected to mask the N4-amino group of the cytosine ring in ara-C and subsequently a peptidomimetic prodrug, L-valyl-ara-C was synthesized as illustrated in Figure 1. L-Valyl-ara-C was obtained as white fluffy powder and its purity was ‡ 98% as determined by HPLC.…”

Section: Synthesis Of L-valyl-ara-cmentioning

confidence: 99%

Enhanced cellular uptake of Ara-C via a peptidomimetic prodrug, L-valyl-ara-C in Caco-2 cells

Cheon

Hong

Han

2006

Journal of Pharmacy and Pharmacology

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This study aimed to investigate the gastrointestinal stability and the cellular uptake characteristics of L-valyl-ara-C, a peptidomimetic prodrug of ara-C (cytarabine). After the synthesis of Lvalyl-ara-C via the incorporation of L-valine into the N4-amino group of the cytosine ring in ara-C, the gastrointestinal stability of L-valyl-ara-C was examined using artificial gastric juice and artificial intestinal fluids. The cellular uptake characteristics of L-valyl-ara-C were also examined in Caco-2 cells. The disappearance half-life of L-valyl-ara-C was 2.2 h in artificial gastric juice, while the degradation of L-valyl-ara-C was negligible in artificial intestinal fluid and also in the supernatant above the Caco-2 cell monolayer during the 2-h incubation. The cellular accumulation of L-valyl-ara-C was 5-fold higher than that of ara-C in Caco-2 cells. Furthermore, the cellular uptake of L-valyl-ara-C did not increase proportionally to the increase in drug concentration. The cellular accumulation of L-valyl-ara-C was significantly reduced in the presence of uridine, p-aminohippurate, tetraethylammonium and small dipeptides, while it was not changed in the presence of L-valine and benzoic acid, suggesting that L-valyl-ara-C could interact with multiple uptake transporters, including peptide transporters, organic anion and cation transporters and nucleoside transporters, but might not interact with amino acid transporters. In conclusion, L-valyl-ara-C could be effective to improve the oral absorption of ara-C via the carrier-mediated transport pathway.

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Amino Acid Ester Prodrugs of Acyclovir

Cited by 202 publications

References 25 publications

Targeted delivery to PEPT1-overexpressing cells: Acidic, basic, and secondary floxuridine amino acid ester prodrugs

Targeted delivery to PEPT1-overexpressing cells: Acidic, basic, and secondary floxuridine amino acid ester prodrugs

The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension

Enhanced cellular uptake of Ara-C via a peptidomimetic prodrug, L-valyl-ara-C in Caco-2 cells

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