Drug inhibition of Gly-Sar uptake and hPepT1 localization using hPepT1-GFP fusion protein

Sun, Duxin; Landowski, Christopher P.; Chu, Xiaoyan; Wallsten, Richard; Fleisher, David; Amidon, Gordon L.; Komorowski, Thomas E.

doi:10.1208/ps030102

Cited by 18 publications

(14 citation statements)

References 19 publications

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“…7). Sun et al (2001) detected hPEPT1-GFP at apical and basolateral membranes in Caco-2 cells. It was reported that hPEPT1 was present in the plasma membrane and intracellular vesicular structures of AsPC-1 and Capan-2 cells by Gonzalez et al (1998).…”

Section: Drug Delivery To the Liver By Hpept1 Heterologous Expressionmentioning

confidence: 88%

Enhanced Delivery of Drugs to the Liver by Adenovirus-Mediated Heterologous Expression of the Human Oligopeptide Transporter PEPT1

Toyobuku

Sai²,

Tamai³

et al. 2002

J Pharmacol Exp Ther

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Section: Drug Delivery To the Liver By Hpept1 Heterologous Expressionmentioning

confidence: 88%

Enhanced Delivery of Drugs to the Liver by Adenovirus-Mediated Heterologous Expression of the Human Oligopeptide Transporter PEPT1

Toyobuku

Sai²,

Tamai³

et al. 2002

J Pharmacol Exp Ther

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“…The PEPT1 transporter has been extensively studied for its role in transporting a variety of peptides and peptidomimetic compounds . This 708 amino acid transporter has been functionally expressed in a variety of cell systems including Chinese hamster ovary cells and HeLa cells (Covitz et al, 1996;Han et al, 1999;Surendran et al, 1999;Chu et al, 2001;Sun et al, 2001). It was demonstrated that PEPT1 in overexpressed cells transported several di-and tripeptides as well as a few peptidomimetic compounds but was not capable of transporting amino acids.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression in the Human Intestine and Correlation with Oral Valacyclovir Pharmacokinetic Parameters

Landowski

Sun

Foster

et al. 2003

J Pharmacol Exp Ther

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The transport of valacyclovir, the L-valyl ester of acyclovir, has been suggested to be mediated by several carrier-mediated pathways in cell culture and animal models. The role and importance of these transporters in modulating valacyclovir absorption in humans has not been determined, however. Recent advances in genomic technology have facilitated the rapid and simultaneous determination of global mRNA expression profiles for thousands of genes in tissue biopsies directly associated with the absorption process, thereby dramatically increasing the value of studies in humans. In this article, we describe correlations of pharmacokinetic parameters following oral valacyclovir or acyclovir administration with expression levels of intestinal genes in humans. Highly positive and significant correlations were observed with 4F2hc, an activator of cationpreferring amino acid transport systems, and human oligopeptide transporter (HPT1), an oligopeptide transporter expressed at higher levels in the human intestine compared with oligopeptide transporter (PEPT1). The validation of HPT1 microarray data with reverse transcription-polymerase chain reaction and the enhanced valacyclovir uptake in HeLa/HPT1 cells suggest that the role of HPT1 in transport of peptides and peptidomimetics drugs needs to be examined in more detail. The interrelation of 4F2hc and HPT1 in transport may be of interest. No significant correlations of valacyclovir pharmacokinetic parameters with PEPT1 and with organic cation or anion transporter expression levels were observed. The highly negative correlations observed with known efflux pumps such as MDR1 (Pglycoprotein) and MRP2 (cMOAT), as well as with the CYP450 IIIA subfamily may indicate that these proteins may regulate the cellular accumulation and metabolism of acyclovir.The enhancement in oral valacyclovir bioavailability, the L-valyl ester of the antiviral agent acyclovir, has been attributed to its enhanced permeation across the intestine compared with acyclovir. The early acyclovir disposition studies following oral administration of the L-and D-valyl stereoisomers to rats clearly indicated stereoselective absorption, thus suggesting a carrier-mediated mechanism (Beauchamp et al

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“…Interestingly, clustered intracellular expression was also observed in hPepT1-expressing MDCK cells. Although intracellular existence of a low-affinity peptide transporter was previously suggested (Bockman et al, 1997;Zhou et al, 2000), no conclusive evidence is available to support hPepT1 expression in intracellular compartments (Sun et al, 2001). The exact intracellular localization of hPepT1 within epithelial cells requires further investigation.…”

Section: Downloaded Frommentioning

confidence: 91%

Interactions of Amoxicillin and Cefaclor With Human Renal Organic Anion and Peptide Transporters

Li¹,

Anderson²,

Phillips³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Amoxicillin and cefaclor are two of the widely used ␤-lactam antibiotics in the treatment of urinary tract infections. Both drugs are eliminated mainly by the kidney and rely on renal excretion to exert their antibacterial activities in the urinary tract. Previous studies have suggested the involvement of organic anion and oligopeptide transporters in membrane transport of ␤-lactams. The objective of the current study was to examine the kinetics of amoxicillin and cefaclor interactions with human renal transporters human organic anion transporter 1 (hOAT1), human peptide transporter 1 (hPepT1), and human peptide transporter 2 (hPepT2) in detail, both as substrates and as inhibitors. Using fluorescence protein tagging and cell sorting, we established Madin-Darby canine kidney cell lines stably expressing highly functional hOAT1, hPepT1, and hPepT2. Amoxicillin and cefaclor inhibited hOAT1-mediated [ 3 H]para-aminohippuric acid uptake (K i ‫؍‬ 11.0 and 1.15 mM, respectively). However, our uptake study revealed that neither drug was transported by hOAT1. Amoxicillin and cefaclor competitively inhibited hPepT2-mediated [ 3 H]glycylsarcosine uptake (K i ‫؍‬ 733 and 65 M, respectively), whereas much lower affinity for hPepT1 was observed with both antibiotics. Direct uptake studies demonstrated that amoxicillin and cefaclor were transported by hPepT1 and hPepT2. Kinetic analysis showed that hPepT2-mediated uptake of both drugs was saturable with K m of 1.04 mM for amoxicillin and 70.2 M for cefaclor. hPepT2, and to a lesser extent hPepT1, may play an important role in apical transport of amoxicillin and cefaclor in the renal tubule. hOAT1, in contrast, is not involved in basolateral uptake of these antibiotics.

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Drug inhibition of Gly-Sar uptake and hPepT1 localization using hPepT1-GFP fusion protein

Cited by 18 publications

References 19 publications

Enhanced Delivery of Drugs to the Liver by Adenovirus-Mediated Heterologous Expression of the Human Oligopeptide Transporter PEPT1

Enhanced Delivery of Drugs to the Liver by Adenovirus-Mediated Heterologous Expression of the Human Oligopeptide Transporter PEPT1

Gene Expression in the Human Intestine and Correlation with Oral Valacyclovir Pharmacokinetic Parameters

Interactions of Amoxicillin and Cefaclor With Human Renal Organic Anion and Peptide Transporters

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