Prodrugs of purine and pyrimidine analogues for the intestinal di/tri-peptide transporter PepT1: affinity for hPepT1 in Caco-2 cells, drug release in aqueous media and in vitro metabolism

Thomsen, Anne Engelbrecht; Friedrichsen, Gerda Marie; Sørensen, Arne Hagsten; Andersen, Rikke; Nielsen, Carsten Uhd; Brodin, Birger; Begtrup, Mikael; Frøkjær, Sven; Steffansen, Bente

doi:10.1016/s0168-3659(02)00413-3

Cited by 29 publications

(18 citation statements)

References 23 publications

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“…Targetting the carrier-mediated transport process is another successful prodrug strategy that has been shown to enhance intestinal absorption (Thomsen et al 2003;Ettmayer et al 2004;Steffansen et al 2004). For example, oligopeptide transporters are responsible for the active absorption of -lactam antibiotics, the ACE inhibitor enalapril, valaciclovir and valganciclovir.…”

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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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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“…In addition to its naturally occurring substrates, di-and tripeptides, PEPT1 is capable of actively transporting a variety of chemically diverse compounds, including ␤-lactam antibiotics, renin inhibitors, and angiotensin-converting enzyme inhibitors (Rubio-Aliaga and Daniel, 2002). Because of the broad substrate specificity of PEPT1, a prodrug approach, by which a poorly bioavailable drug is modified to be transported by PEPT1, has been intensively investigated as a promising strategy to improve oral absorption of certain molecules (Balimane et al, 1998;Steffansen et al, 1999;Friedrichsen et al, 2001;Thomsen et al, 2003). It is anticipated that with the unfolding of substrate structural requirements of PEPT1, more rationally designed peptidomimetic molecules and prodrugs targeting to PEPT1 will be generated in the future.…”

mentioning

confidence: 99%

Genetic Polymorphisms in Human Proton-Dependent Dipeptide Transporter PEPT1: Implications for the Functional Role of Pro⁵⁸⁶

Zhang¹,

Fu²,

Pak³

et al. 2004

J Pharmacol Exp Ther

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The human proton-dependent dipeptide transporter (PEPT1, gene SLC15A1) is important for intestinal absorption of di-and tripeptides and a variety of peptidomimetic compounds. Using a DNA polymorphism discovery panel of 44 ethnically diverse individuals, nine nonsynonymous and four synonymous coding-region single-nucleotide polymorphisms (SNPs) were identified in PEPT1. HeLa cells were transiently transfected with plasmids constructed by site-directed mutagenesis for each of the nine nonsynonymous variants. Quantitative polymerase chain reaction showed that the mRNA transcription level of all of the mutants was comparable with the mRNA transcription level of the reference sequence in transfected HeLa cells. Functional analysis in transiently transfected HeLa cells revealed that all nonsynonymous variants retained similar pH-dependent activity and K t values for [glycyl-1,2-14 C]glycylsarcosine (GlySar) uptake as the reference PEPT1. In addition, a group of seven peptide-like drugs showed inhibitory effect on Gly-Sar uptake by these variants comparable with the reference, suggesting conserved drug recognition. Of the nine nonsynonymous SNPs, a single SNP (P586L) demonstrated significantly reduced transport capacity as evidenced by a much lower V max value. This was consistent with lower immunoactive protein level (Western analysis) and lower plasma membrane expression (immunocytochemical analysis). Therefore, Pro 586 may have profound effect on PEPT1 translation, degradation, and/or membrane insertion.

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“…Prodrugs that have amino acids as transport groups present three-to ten-fold greater passage through the membrane than the original drug. Thus, the greater absorption of valacyclovir compared to acyclovir is due to the presence of the amino acid (valine) (Ettmayer et al, 2004;Thomsen et al, 2003;Thomsen et al, 2004;Vabeno et al, 2004). The presence of valine enables the passage of the drug through membranes by means of specific amino acid transporters (hPEPT 1 and 2) (Andersen et al, 2006;Steingrimsdottir et al, 2000;Steffansen et al, 2004;Sugawara et al, 2000).…”

Section: Antiviralsmentioning

confidence: 99%

Prodrugs available on the Brazilian pharmaceutical market and their corresponding bioactivation pathways

Parise-Filho

Polli

Barberato‐Filho

et al. 2010

Braz. J. Pharm. Sci.

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The aim of this paper was to emphasize the importance of prodrug design to therapy, by examining examples available on the Brazilian pharmaceutical market. The principles of prodrug design are briefly discussed herein. Examples of prodrugs from many important therapeutic classes are shown and their advantages relative to the drugs they are derived from are also discussed. Considering the importance of these therapeutic classes, from both therapy and economic standpoints, prodrug design is a very valuable aspect in the research of new drugs and for the pharmaceutical industry as a whole.Uniterms: Prodrug design. Molecular modification. Drug development.O objetivo do trabalho foi ressaltar a importância do planejamento de pró-fármacos para a terapia, por meio de exemplos disponíveis no mercado farmacêutico brasileiro. Os princípios da latenciação são sucintamente discutidos. Apresentam-se exemplos de pró-fármacos de muitas classes terapêuticas importantes e as vantagens relativas aos fármacos dos quais derivam são, também, discutidas. Considerando-se a importância dessas classes terapêuticas, tanto do aspecto terapêutico quanto do econômico, o planejamento de pró-fármacos representa aspecto de grande valor na busca de novos fármacos e na indústria farmacêutica como um todo.Uniterms: Pró-fármacos/planejamento Fármacos/latenciação. Modificação molecular. Fármacos/ desenvolvimento.

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Prodrugs of purine and pyrimidine analogues for the intestinal di/tri-peptide transporter PepT1: affinity for hPepT1 in Caco-2 cells, drug release in aqueous media and in vitro metabolism

Cited by 29 publications

References 23 publications

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

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

Genetic Polymorphisms in Human Proton-Dependent Dipeptide Transporter PEPT1: Implications for the Functional Role of Pro⁵⁸⁶

Prodrugs available on the Brazilian pharmaceutical market and their corresponding bioactivation pathways

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Prodrugs of purine and pyrimidine analogues for the intestinal di/tri-peptide transporter PepT1: affinity for hPepT1 in Caco-2 cells, drug release in aqueous media and in vitro metabolism

Cited by 29 publications

References 23 publications

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

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

Genetic Polymorphisms in Human Proton-Dependent Dipeptide Transporter PEPT1: Implications for the Functional Role of Pro586

Prodrugs available on the Brazilian pharmaceutical market and their corresponding bioactivation pathways

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Product

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About

Genetic Polymorphisms in Human Proton-Dependent Dipeptide Transporter PEPT1: Implications for the Functional Role of Pro⁵⁸⁶