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Michael G. Sarr - One of the best experts on this subject based on the ideXlab platform.

  • Intestinal Adaptation for OligoPeptide Absorption via PepT1 After Massive (70%) Mid-Small Bowel Resection
    Journal of Gastrointestinal Surgery, 2011
    Co-Authors: Srivats Madhavan, Jeffrey S. Scow, Rizwan M. Chaudhry, Munenori Nagao, Judith A. Duenes, Ye Zheng, Michael G. Sarr
    Abstract:

    Introduction Proteins are absorbed primarily as short Peptides via Peptide Transporter 1 (PepT1). Hypothesis Intestinal adaptation for Peptide absorption after massive mid-small intestinal resection occurs by increased expression of PepT1 in the remnant small intestine and colon. Methods Peptide uptake was measured in duodenum, jejunum, ileum, and colon using glycyl-sarcosine 1 week ( n  = 9) and 4 weeks ( n  = 11) after 70% mid-small bowel resection and in corresponding segments from unoperated rats ( n  = 12) and after transection and reanastomosis of jejunum and ileum ( n  = 8). Expression of PepT1 (mRNA, protein) and villus height were measured. Results Intestinal transection/reanastomosis did not alter gene expression. Compared to non-operated controls, 70% mid-small bowel resection increased jejunal Peptide uptake ( p  

  • Intestinal adaptation for oligoPeptide absorption via PepT1 after massive (70%) mid-small bowel resection.
    Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract, 2010
    Co-Authors: Srivats Madhavan, Jeffrey S. Scow, Rizwan M. Chaudhry, Munenori Nagao, Judith A. Duenes, Ye Zheng, Michael G. Sarr
    Abstract:

    Proteins are absorbed primarily as short Peptides via Peptide Transporter 1 (PepT1). Intestinal adaptation for Peptide absorption after massive mid-small intestinal resection occurs by increased expression of PepT1 in the remnant small intestine and colon. Peptide uptake was measured in duodenum, jejunum, ileum, and colon using glycyl-sarcosine 1 week (n = 9) and 4 weeks (n = 11) after 70% mid-small bowel resection and in corresponding segments from unoperated rats (n = 12) and after transection and reanastomosis of jejunum and ileum (n = 8). Expression of PepT1 (mRNA, protein) and villus height were measured. Intestinal transection/reanastomosis did not alter gene expression. Compared to non-operated controls, 70% mid-small bowel resection increased jejunal Peptide uptake (p 

  • 590 Intestinal Adaptation of OligoPeptide Absorption via PepT1 After Massive (70%) Mid Small Bowel Resection
    Gastroenterology, 2010
    Co-Authors: Srivats Madhavan, Jeffrey S. Scow, Munenori Nagao, Judith A. Duenes, Ye Zheng, Michael G. Sarr
    Abstract:

    Introduction Proteins are absorbed primarily as short Peptides via Peptide Transporter 1 (PepT1).

  • Role of Vagal Innervation in Diurnal Rhythm of Intestinal Peptide Transporter 1 (PEPT1)
    Journal of Gastrointestinal Surgery, 2009
    Co-Authors: Hisham G. Qandeel, Jeffrey S. Scow, Judith A. Duenes, Ye Zheng, Fernando Alonso, David J. Hernandez, Michael G. Sarr
    Abstract:

    Background Protein is absorbed predominantly as di/triPeptides via H^+/Peptide coTransporter-1 (PEPT1). We demonstrated previously diurnal variations in expression and function of duodenal and jejunal but not ileal PEPT1; neural regulation of this pattern is unexplored. Hypothesis Complete abdominal vagotomy abolishes diurnal variations in gene expression and transport function of PEPT1. Methods Twenty-four rats maintained in a 12-h light/dark room [6AM–6PM] underwent abdominal vagotomy; 24 other rats were controls. Four weeks later, mucosal levels of mRNA and protein were measured at 9AM, 3PM, 9PM, and 3AM ( n  = 6 each) by quantitative real-time PCR and Western blots, respectively; Transporter-mediated uptake of diPeptide (Gly–Sar) was measured by the everted-sleeve technique. Results Diurnal variation in mRNA, as in controls, was retained post-vagotomy in duodenum and jejunum (peak at 3PM, p   0.3). Similar to controls, maximal uptake was in jejunum after vagotomy ( V _max, nmol/cm/min: jejunum vs. duodenum and ileum; 163 vs. 88 and 71 at 3AM; p  

  • Role of vagal innervation in diurnal rhythm of intestinal Peptide Transporter 1 (PEPT1)
    Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract, 2009
    Co-Authors: Hisham G. Qandeel, Jeffrey S. Scow, Judith A. Duenes, Ye Zheng, Fernando Alonso, David J. Hernandez, Michael G. Sarr
    Abstract:

    Background Protein is absorbed predominantly as di/triPeptides via H+/Peptide coTransporter-1 (PEPT1). We demonstrated previously diurnal variations in expression and function of duodenal and jejunal but not ileal PEPT1; neural regulation of this pattern is unexplored.

David E Smith - One of the best experts on this subject based on the ideXlab platform.

  • impact of Peptide Transporter 1 on the intestinal absorption and pharmacokinetics of valacyclovir after oral dose escalation in wild type and pept1 knockout mice
    Drug Metabolism and Disposition, 2013
    Co-Authors: Bei Yang, Yongjun Hu, David E Smith
    Abstract:

    The primary objective of this study was to determine the in vivo absorption properties of valacyclovir, including the potential for saturable proton-coupled oligoPeptide Transporter 1 (PepT1)-mediated intestinal uptake, after escalating oral doses of prodrug within the clinical dose range. A secondary aim was to characterize the role of PepT1 on the tissue distribution of its active metabolite, acyclovir. [3H]Valacyclovir was administered to wild-type (WT) and PepT1 knockout (KO) mice by oral gavage at doses of 10, 25, 50, and 100 nmol/g. Serial blood samples were collected over 180 minutes, and tissue distribution studies were performed 20 minutes after a 25-nmol/g oral dose of valacyclovir. We found that the Cmax and area under the curve (AUC)0–180 of acyclovir were 4- to 6-fold and 2- to 3-fold lower, respectively, in KO mice for all four oral doses of valacyclovir. The time to peak concentration of acyclovir was 3- to 10-fold longer in KO compared with WT mice. There was dose proportionality in the Cmax and AUC0–180 of acyclovir in WT and KO mice over the valacyclovir oral dose range of 10–100 nmol/g (i.e., linear absorption kinetics). No differences were observed in the peripheral tissue distribution of acyclovir once these tissues were adjusted for differences in perfusing drug concentrations in the systemic circulation. In contrast, some differences were observed between genotypes in the concentrations of acyclovir in the distal intestine. Collectively, the findings demonstrate a critical role of intestinal PepT1 in improving the rate and extent of oral absorption for valacyclovir. Moreover, this study provides definitive evidence for the rational development of a PepT1-targeted prodrug strategy.

  • Significance of Peptide Transporter 1 in the Intestinal Permeability of Valacyclovir in Wild-Type and PepT1 Knockout Mice
    Drug Metabolism and Disposition, 2012
    Co-Authors: Bei Yang, David E Smith
    Abstract:

    The purpose of this study was to quantitatively determine the contribution of PepT1 [Peptide Transporter 1 (SLC15A1)] to the intestinal permeability of valacyclovir, an ester prodrug of the antiviral drug acyclovir. In situ single-pass intestinal perfusions were employed (pH 6.5 × 90 minutes) to assess the effective permeability (Peff) of 100 μM [3H]valacyclovir in wild-type and PepT1 knockout mice. Acyclovir pharmacokinetics was also evaluated after oral administration of 25 nmol/g valacyclovir. In wild-type mice, jejunal uptake of valacyclovir was best described by both saturable (Km = 10.2 mM) and nonsaturable components where the saturable pathway accounted for 82% of total transport. Valacyclovir Peff was 2.4 × 10−4 cm/s in duodenum, 1.7 × 10−4 cm/s in jejunum, 2.1 × 10−4 cm/s in ileum, and 0.27 × 10−4 cm/s in colon. In Pept1 knockout mice, Peff values were about 10% of that in wild-type animals for these small intestinal segments. Valacyclovir Peff was similar in the colon of both genotypes. There were no differences in valacyclovir Peff between any of the intestinal segments of PepT1 knockout mice. Valacyclovir Peff was significantly reduced by the diPeptide glycylsarcosine and the aminocephalosporin cefadroxil, but not by the amino acids l-valine or l-histidine, the organic acid p-aminohippurate, or the organic base tetraethylammonium (all at 25 mM). PepT1 ablation resulted in 3- to 5-fold reductions in the in vivo rate and extent of valacyclovir absorption. Our findings conclusively demonstrate, using in situ and in vivo validations in genetically modified mice, that PepT1 has a major influence in improving the oral absorption of valacyclovir.

Ye Zheng - One of the best experts on this subject based on the ideXlab platform.

  • Intestinal Adaptation for OligoPeptide Absorption via PepT1 After Massive (70%) Mid-Small Bowel Resection
    Journal of Gastrointestinal Surgery, 2011
    Co-Authors: Srivats Madhavan, Jeffrey S. Scow, Rizwan M. Chaudhry, Munenori Nagao, Judith A. Duenes, Ye Zheng, Michael G. Sarr
    Abstract:

    Introduction Proteins are absorbed primarily as short Peptides via Peptide Transporter 1 (PepT1). Hypothesis Intestinal adaptation for Peptide absorption after massive mid-small intestinal resection occurs by increased expression of PepT1 in the remnant small intestine and colon. Methods Peptide uptake was measured in duodenum, jejunum, ileum, and colon using glycyl-sarcosine 1 week ( n  = 9) and 4 weeks ( n  = 11) after 70% mid-small bowel resection and in corresponding segments from unoperated rats ( n  = 12) and after transection and reanastomosis of jejunum and ileum ( n  = 8). Expression of PepT1 (mRNA, protein) and villus height were measured. Results Intestinal transection/reanastomosis did not alter gene expression. Compared to non-operated controls, 70% mid-small bowel resection increased jejunal Peptide uptake ( p  

  • Intestinal adaptation for oligoPeptide absorption via PepT1 after massive (70%) mid-small bowel resection.
    Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract, 2010
    Co-Authors: Srivats Madhavan, Jeffrey S. Scow, Rizwan M. Chaudhry, Munenori Nagao, Judith A. Duenes, Ye Zheng, Michael G. Sarr
    Abstract:

    Proteins are absorbed primarily as short Peptides via Peptide Transporter 1 (PepT1). Intestinal adaptation for Peptide absorption after massive mid-small intestinal resection occurs by increased expression of PepT1 in the remnant small intestine and colon. Peptide uptake was measured in duodenum, jejunum, ileum, and colon using glycyl-sarcosine 1 week (n = 9) and 4 weeks (n = 11) after 70% mid-small bowel resection and in corresponding segments from unoperated rats (n = 12) and after transection and reanastomosis of jejunum and ileum (n = 8). Expression of PepT1 (mRNA, protein) and villus height were measured. Intestinal transection/reanastomosis did not alter gene expression. Compared to non-operated controls, 70% mid-small bowel resection increased jejunal Peptide uptake (p 

  • 590 Intestinal Adaptation of OligoPeptide Absorption via PepT1 After Massive (70%) Mid Small Bowel Resection
    Gastroenterology, 2010
    Co-Authors: Srivats Madhavan, Jeffrey S. Scow, Munenori Nagao, Judith A. Duenes, Ye Zheng, Michael G. Sarr
    Abstract:

    Introduction Proteins are absorbed primarily as short Peptides via Peptide Transporter 1 (PepT1).

  • Role of Vagal Innervation in Diurnal Rhythm of Intestinal Peptide Transporter 1 (PEPT1)
    Journal of Gastrointestinal Surgery, 2009
    Co-Authors: Hisham G. Qandeel, Jeffrey S. Scow, Judith A. Duenes, Ye Zheng, Fernando Alonso, David J. Hernandez, Michael G. Sarr
    Abstract:

    Background Protein is absorbed predominantly as di/triPeptides via H^+/Peptide coTransporter-1 (PEPT1). We demonstrated previously diurnal variations in expression and function of duodenal and jejunal but not ileal PEPT1; neural regulation of this pattern is unexplored. Hypothesis Complete abdominal vagotomy abolishes diurnal variations in gene expression and transport function of PEPT1. Methods Twenty-four rats maintained in a 12-h light/dark room [6AM–6PM] underwent abdominal vagotomy; 24 other rats were controls. Four weeks later, mucosal levels of mRNA and protein were measured at 9AM, 3PM, 9PM, and 3AM ( n  = 6 each) by quantitative real-time PCR and Western blots, respectively; Transporter-mediated uptake of diPeptide (Gly–Sar) was measured by the everted-sleeve technique. Results Diurnal variation in mRNA, as in controls, was retained post-vagotomy in duodenum and jejunum (peak at 3PM, p   0.3). Similar to controls, maximal uptake was in jejunum after vagotomy ( V _max, nmol/cm/min: jejunum vs. duodenum and ileum; 163 vs. 88 and 71 at 3AM; p  

  • Role of vagal innervation in diurnal rhythm of intestinal Peptide Transporter 1 (PEPT1)
    Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract, 2009
    Co-Authors: Hisham G. Qandeel, Jeffrey S. Scow, Judith A. Duenes, Ye Zheng, Fernando Alonso, David J. Hernandez, Michael G. Sarr
    Abstract:

    Background Protein is absorbed predominantly as di/triPeptides via H+/Peptide coTransporter-1 (PEPT1). We demonstrated previously diurnal variations in expression and function of duodenal and jejunal but not ileal PEPT1; neural regulation of this pattern is unexplored.

Judith A. Duenes - One of the best experts on this subject based on the ideXlab platform.

  • Intestinal Adaptation for OligoPeptide Absorption via PepT1 After Massive (70%) Mid-Small Bowel Resection
    Journal of Gastrointestinal Surgery, 2011
    Co-Authors: Srivats Madhavan, Jeffrey S. Scow, Rizwan M. Chaudhry, Munenori Nagao, Judith A. Duenes, Ye Zheng, Michael G. Sarr
    Abstract:

    Introduction Proteins are absorbed primarily as short Peptides via Peptide Transporter 1 (PepT1). Hypothesis Intestinal adaptation for Peptide absorption after massive mid-small intestinal resection occurs by increased expression of PepT1 in the remnant small intestine and colon. Methods Peptide uptake was measured in duodenum, jejunum, ileum, and colon using glycyl-sarcosine 1 week ( n  = 9) and 4 weeks ( n  = 11) after 70% mid-small bowel resection and in corresponding segments from unoperated rats ( n  = 12) and after transection and reanastomosis of jejunum and ileum ( n  = 8). Expression of PepT1 (mRNA, protein) and villus height were measured. Results Intestinal transection/reanastomosis did not alter gene expression. Compared to non-operated controls, 70% mid-small bowel resection increased jejunal Peptide uptake ( p  

  • Intestinal adaptation for oligoPeptide absorption via PepT1 after massive (70%) mid-small bowel resection.
    Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract, 2010
    Co-Authors: Srivats Madhavan, Jeffrey S. Scow, Rizwan M. Chaudhry, Munenori Nagao, Judith A. Duenes, Ye Zheng, Michael G. Sarr
    Abstract:

    Proteins are absorbed primarily as short Peptides via Peptide Transporter 1 (PepT1). Intestinal adaptation for Peptide absorption after massive mid-small intestinal resection occurs by increased expression of PepT1 in the remnant small intestine and colon. Peptide uptake was measured in duodenum, jejunum, ileum, and colon using glycyl-sarcosine 1 week (n = 9) and 4 weeks (n = 11) after 70% mid-small bowel resection and in corresponding segments from unoperated rats (n = 12) and after transection and reanastomosis of jejunum and ileum (n = 8). Expression of PepT1 (mRNA, protein) and villus height were measured. Intestinal transection/reanastomosis did not alter gene expression. Compared to non-operated controls, 70% mid-small bowel resection increased jejunal Peptide uptake (p 

  • 590 Intestinal Adaptation of OligoPeptide Absorption via PepT1 After Massive (70%) Mid Small Bowel Resection
    Gastroenterology, 2010
    Co-Authors: Srivats Madhavan, Jeffrey S. Scow, Munenori Nagao, Judith A. Duenes, Ye Zheng, Michael G. Sarr
    Abstract:

    Introduction Proteins are absorbed primarily as short Peptides via Peptide Transporter 1 (PepT1).

  • Role of Vagal Innervation in Diurnal Rhythm of Intestinal Peptide Transporter 1 (PEPT1)
    Journal of Gastrointestinal Surgery, 2009
    Co-Authors: Hisham G. Qandeel, Jeffrey S. Scow, Judith A. Duenes, Ye Zheng, Fernando Alonso, David J. Hernandez, Michael G. Sarr
    Abstract:

    Background Protein is absorbed predominantly as di/triPeptides via H^+/Peptide coTransporter-1 (PEPT1). We demonstrated previously diurnal variations in expression and function of duodenal and jejunal but not ileal PEPT1; neural regulation of this pattern is unexplored. Hypothesis Complete abdominal vagotomy abolishes diurnal variations in gene expression and transport function of PEPT1. Methods Twenty-four rats maintained in a 12-h light/dark room [6AM–6PM] underwent abdominal vagotomy; 24 other rats were controls. Four weeks later, mucosal levels of mRNA and protein were measured at 9AM, 3PM, 9PM, and 3AM ( n  = 6 each) by quantitative real-time PCR and Western blots, respectively; Transporter-mediated uptake of diPeptide (Gly–Sar) was measured by the everted-sleeve technique. Results Diurnal variation in mRNA, as in controls, was retained post-vagotomy in duodenum and jejunum (peak at 3PM, p   0.3). Similar to controls, maximal uptake was in jejunum after vagotomy ( V _max, nmol/cm/min: jejunum vs. duodenum and ileum; 163 vs. 88 and 71 at 3AM; p  

  • Role of vagal innervation in diurnal rhythm of intestinal Peptide Transporter 1 (PEPT1)
    Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract, 2009
    Co-Authors: Hisham G. Qandeel, Jeffrey S. Scow, Judith A. Duenes, Ye Zheng, Fernando Alonso, David J. Hernandez, Michael G. Sarr
    Abstract:

    Background Protein is absorbed predominantly as di/triPeptides via H+/Peptide coTransporter-1 (PEPT1). We demonstrated previously diurnal variations in expression and function of duodenal and jejunal but not ileal PEPT1; neural regulation of this pattern is unexplored.

David C. Smith - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacokinetics of gemcitabine and its amino acid ester prodrug following intravenous and oral administrations in mice
    Biochemical pharmacology, 2020
    Co-Authors: Brian R. Thompson, Jian Shi, Hao Jie Zhu, David C. Smith
    Abstract:

    Abstract Gemcitabine is an intravenously administered anti-cancer nucleoside analogue. Systemic exposure following oral administration of gemcitabine is limited by extensive first-pass metabolism via cytidine deaminase (CDA) and potentially by saturation of nucleoside Transporter-mediated intestinal uptake. An amino acid ester prodrug of gemcitabine, 5′-l-valyl-gemcitabine (V-Gem), was previously shown to be a substrate of the intestinally expressed Peptide Transporter 1 (PEPT1) and stable against CDA-mediated metabolism. However, preliminary studies did not evaluate the in vivo oral performance of V-Gem as compared to parent drug. In the present study, we evaluated the pharmacokinetics and in vivo oral absorption of gemcitabine and V-Gem following intravenous and oral administrations in mice. These studies revealed that V-Gem undergoes rapid systemic elimination (half-life

  • Computing Substrate Selectivity in a Peptide Transporter
    Cell chemical biology, 2016
    Co-Authors: Claire Colas, David C. Smith, Avner Schlessinger
    Abstract:

    The human proton-coupled Peptide Transporter 1 (PepT1) is responsible for the absorption of di- and tri-Peptides from the diet and Peptide-like drugs. In this issue of Cell Chemical Biology, Samsudin et al. (2016) use an integrated computational and experimental approach to provide new insights into understanding substrate selectivity of PepTSt, a prokaryotic homolog of the human PepT1.

  • Effect of Dose Escalation on the In Vivo Oral Absorption and Disposition of Glycylsarcosine in Wild-Type and Pept1 Knockout Mice
    Drug metabolism and disposition: the biological fate of chemicals, 2011
    Co-Authors: Dilara Jappar, David C. Smith
    Abstract:

    This study evaluated the in vivo absorption and disposition of glycylsarcosine (GlySar), after escalating oral doses, in wild-type and Peptide Transporter 1 (Pept1) knockout mice. [3H]GlySar was administered to mice at doses of 1, 10, 100, 1000, and 5000 nmol/g b.wt. Serial blood samples were obtained over 480 min, the plasma was harvested, and the area under the plasma concentration-time curve (AUC) was determined. It was observed that the GlySar AUC was 60, 45, and 30% lower in knockout than wild-type mice when evaluated over 2, 4, and 8 h, respectively (p

  • Peptide Transporter 1 Is Responsible for Intestinal Uptake of the DiPeptide Glycylsarcosine: Studies in Everted Jejunal Rings from Wild-type and Pept1 Null Mice
    Journal of pharmaceutical sciences, 2010
    Co-Authors: David C. Smith
    Abstract:

    ABSTRACT The purpose of this study was to determine the relative importance of Peptide Transporter 1 (PEPT1) in the uptake of Peptides/mimetics from mouse small intestine, using glycylsarcosine (GlySar). After isolating jejunal tissue from wild-type and Pept1 null mice, 2 cm intestinal segments were everted and mounted on glass rods for tissue uptake studies. [ 14 C]GlySar (4 μM) was studied as a function of time, temperature, sodium and pH, concentration, and potential inhibitors. Compared with wild-type animals, Pept1 null mice exhibited a 78% reduction in GlySar uptake at pH 6.0 at 37°C. GlySar uptake showed pH dependence, with peak values between pH 6.0 and 6.5 in wild-type animals, whereas no such tendency was observed in Pept1 null mice. GlySar exhibited Michaelis–Menten uptake kinetics and a minor nonsaturable component in wild-type animals. In contrast, GlySar uptake occurred only by a nonsaturable process in Pept1 null mice. GlySar uptake was significantly inhibited by diPeptides, aminocephalosporins, angiotensin-converting enzyme inhibitors, and the antiviral prodrug valacyclovir; these inhibitors had little, if any, effect on the uptake of GlySar in Pept1 null mice. The findings demonstrate that PEPT1 plays a critical role in the uptake of GlySar in jejunum and suggest that PEPT1 is the major Transporter responsible for the intestinal absorption of small Peptides.