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Han, Hyo-Kyung; Oh, Doo-Man; Amidon, Gordon L.

doi:10.1023/a:1011945420235

Cited by 86 publications

(34 citation statements)

References 15 publications

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“…The antivirals valacyclovir and valganciclovir are early examples for the success of amino acid ester prodrug strategies [21,42]. The improved oral bioavailability of these anti-virals has been attributed to their enhanced affinity to transporters [3,4,43–45]. A variety of amino acid, dipeptide and tripeptide have been investigated to improve the oral absorption via intake transporters as a part of prodrug approaches [16,17,22–24,46–49].…”

Section: Discussionmentioning

confidence: 99%

The development of orally administrable gemcitabine prodrugs with d-enantiomer amino acids: Enhanced membrane permeability and enzymatic stability

Tsume

Incecayir

Song³

et al. 2014

European Journal of Pharmaceutics and Biopharmaceutics

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Gemcitabine prodrugs with D- and L-configuration amino acids were synthesized and their chemical stability in buffers, resistance to glycosidic bond metabolism, enzymatic activation, permeability in Caco-2 cells and mouse intestinal membrane, anti-proliferation activity in cancer cell were determined and compared to that of parent drug, gemcitabine. Prodrugs containing D-configuration amino acids were enzymatically more stable than ones with L-configuration amino acids. The activation of all gemcitabine prodrugs was 1.3–17.6-fold faster in cancer cell homogenate than their hydrolysis in buffer, suggesting enzymatic action. The enzymatic activation of amino acid monoester prodrugs containing D-configuration amino acids in cell homogenates was 2.2–10.9-fold slower than one of amino acid monoester prodrugs with L-configuration amino acids. All prodrugs exhibited enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase compared to parent gemcitabine. Gemcitabine prodrugs showed superior the effective permeability in mouse jejunum to gemcitabine. More importantly, the high plasma concentration of D-amino acid gemcitabine prodrugs was observed more than one of L-amino acid gem-citabine prodrugs. In general, the 5′-mono-amino acid monoester gemcitabine prodrugs exhibited higher permeability and uptake than their parent drug, gemcitabine. Cell proliferation assays in AsPC-1 pancreatic ductal cell line indicated that gemcitabine prodrugs were more potent than their parent drug, gemcitabine. The transport and enzymatic profiles of 5′-D-valyl-gemcitabine and 5′-D-phenylalanyl-gem-citabine suggest their potential for increased oral uptake and delayed enzymatic bioconversion as well as enhanced uptake and cytotoxic activity in cancer cells, would facilitate the development of oral dosage form for anti-cancer agents and, hence, improve the quality of life for the cancer patients.

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Section: Discussionmentioning

confidence: 99%

The development of orally administrable gemcitabine prodrugs with d-enantiomer amino acids: Enhanced membrane permeability and enzymatic stability

Tsume

Incecayir

Song³

et al. 2014

European Journal of Pharmaceutics and Biopharmaceutics

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“…The production of amino acid conjugated species has been implicated in the enhanced cellular uptake of daunorubicin. 43) A recent paper has reported on the cellular uptake of amino acid ester prodrugs by a peptide transporter, 44) making entrance into the cell theoretically possible through either active or passive transport.…”

Section: Discussionmentioning

confidence: 99%

Paclitaxel Delivery Systems: The Use of Amino Acid Linkers in the Conjugation of Paclitaxel with Carboxymethyldextran to Create Prodrugs

Sugahara

Kajiki

Kuriyama

et al. 2002

Biological & Pharmaceutical Bulletin

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Paclitaxel (Taxol ® ), an anti-microtubule agent isolated from the trunk bark of the Pacific Yew tree, Taxus brevifolia, 1) shows great promise as an anti-neoplastic agent for a variety of human cancers including breast, ovarian, non small cell lung, head and neck cancers, leukemia, and melanoma. [2][3][4][5][6] Its unique mechanism of action is related to its ability to promote microtubule assembly and inhibit cell replication in the late G2 or M phases of the cell cycle.7) A major problem associated with the administration of paclitaxel is its low solubility in water as well as in most pharmaceutically acceptable solvents. 21,22) and polymer-bound derivatives. 23,24) Although some of the dosage forms can be solubilized to release sufficient quantities of paclitaxel and have shown improved anti-tumor effects in animal models, problems-such as stability-have been observed.25) The use of macromolecules for the targeted delivery of anticancer agents has generated considerable interest regarding enhancing therapeutic efficacy and reducing systemic side effects, and some satisfactory results have been obtained. 26) We previously reported how to prepare carboxymethyldextran (CMDex) and doxorubicin (DXR) conjugates using a peptide linker, and in our evaluation we showed that CMDex with a suitable anionic nature and MW of more than 150 kDa increased retention of the conjugate in blood circulation and increased accumulation of DXR in tumors.27) Furthermore, CMDex-peptide-DXR conjugates containing a gly-gly-phegly spacer were more efficacious in a Walker-256 carcinoma rat model than a free DXR or a conjugate with no spacer. We chose CMDex as a candidate for a paclitaxel carrier since: CMDex is biocompatible; it contains a large number of carboxyl groups for the drug attachment and provides sufficient carrying capacity of the drug; and the resulting CMDex-drug conjugate has a high probability of being water-soluble.In this paper, we examine the synthesis and evaluation of CMDex-paclitaxel conjugates bound with an ester bond and using amino acid linkers, namely, gly, ala, leu, and ile. We also look at how polymeric modification of paclitaxel with CMDex significantly improves water solubility and antitumor activity. The gly linker was introduced into the 2Ј-hydroxyl group to form CMDex-2Ј-gly-paclitaxel and into the 7-hydroxyl group to form CMDex-7-gly-paclitaxel. All other amino acid linkers-ala, leu, and ile-were introduced only into the 2Ј-hydroxyl group of paclitaxel. These were all designed to be water-soluble. The amounts of paclitaxel released from the conjugates during incubation with a buffer and mouse plasma at 37°C were measured by HPLC. We compared this to their in vivo tumor distribution and in vivo anti-tumor effects in a paclitaxel resistant tumor mouse model (colon 26). The tumor and body weights of the mice were monitored after continuous intravenous administration. Paclitaxel was bound via its hydroxyl group to carboxymethyldextran (CMDex, 150 kDa) by means of an amino acid linker; the linker was intr...

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“…Contrarily, rPEPT2 has greater affinity for these antibiotics. Astonishingly, valacyclovir, which is not a peptide, has also been shown to be transported by PEPT with a higher affinity for rPEPT2 [129]. However, the real participation of PEPT in the transport of drugs remains to be studied.…”

Section: Transport Of Peptidesmentioning

confidence: 99%

Renal Tubular Drug Transporters

Launay-Vacher¹,

Izzedine²,

Karie³

et al. 2006

Nephron Physiol

106

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The kidney plays an important role in the elimination of numerous hydrophilic xenobiotics, including drugs, toxins, and endogenous compounds. It has developed high-capacity transport systems to prevent urinary loss of filtered nutrients, as well as electrolytes, and simultaneously to facilitate tubular secretion of a wide range of organic ions. Transport systems for organic anions and cations are primarily involved in the secretion of drugs in renal tubules. The identification and characterization of organic anion and cation transporters have been progressing at the molecular level. To date, many members of the organic anion transporter, organic cation transporter, and organic anion-transporting polypeptide families have been found to mediate the transport of diverse organic ions. It has also been suggested that ATP-dependent primary active transporters such as MDR1/P-glycoprotein and the multidrug resistance-associated protein family function as efflux pumps of renal tubular cells for more hydrophobic molecules and anionic conjugates. Tubular reabsorption of peptide-like drugs such as beta-lactam antibiotics across the brush-border membranes appears to be mediated by two distinct H⁺/peptide cotransporters: PEPT1 and PEPT2. Renal disposition of drugs occurs through interaction with these diverse secretory and absorptive transporters in renal tubules. Studies of the functional characteristics, such as substrate specificity and transport mechanisms, and of the localization of drug transporters could provide information regarding the cellular network involved in renal handling of drugs. Detailed information concerning molecular and cellular aspects of drug transporters expressed in the kidney has facilitated studies of the mechanisms underlying renal disposition as well as transporter-mediated drug interactions.

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Cited by 86 publications

References 15 publications

The development of orally administrable gemcitabine prodrugs with d-enantiomer amino acids: Enhanced membrane permeability and enzymatic stability

The development of orally administrable gemcitabine prodrugs with d-enantiomer amino acids: Enhanced membrane permeability and enzymatic stability

Paclitaxel Delivery Systems: The Use of Amino Acid Linkers in the Conjugation of Paclitaxel with Carboxymethyldextran to Create Prodrugs

Renal Tubular Drug Transporters

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