PepT1-mediated epithelial transport of dipeptides and cephalexin is enhanced by luminal leptin in the small intestine

Buyse, Marion; Berlioz, Françoise; Guilmeau, Sandra; Tsocas, Annick; Voisin, Thierry; Péranzi, Gabriel; Merlin, Didier; Laburthe, Marc; Lewin, M. J. M.; Rozé, C; Bado, André

doi:10.1172/jci200113219

Cited by 40 publications

(42 citation statements)

References 52 publications

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“…It has been previously determined that cephalexin is a substrate of the intestinal dipeptide transporter PEPT1 [15, 16]. Moreover, cephalexin intestinal absorption is primarily mediated by PEPT1 in rats and mice [17, 18]. Our results showed that age modifies the time to cephalexin appearance in the systemic circulation, as Tlag was higher in geriatric animals.…”

Section: Discussionsupporting

confidence: 60%

A Population Pharmacokinetic Approach to Describe Cephalexin Disposition in Adult and Aged Dogs

Prados

Schaiquevich

Kreil

et al. 2014

Veterinary Medicine International

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This study was conducted in order to characterize the pharmacokinetics of orally administered cephalexin to healthy adult and aged dogs, using a population pharmacokinetic approach. Two hundred and eighty-six cephalexin plasma concentrations obtained from previous pharmacokinetic studies were used. Sex, age, pharmaceutical formulation, and breed were evaluated as covariates. A one-compartment model with an absorption lag-time (Tlag) best described the data. The final model included age (adult; aged) on apparent volume of distribution (Vd/F), apparent elimination rate (ke/F), and Tlag; sex (female; male) on ke/F, and breed (Beagle; mixed-breed) on Vd/F. Addition of the covariates to the model explained 78% of the interindividal variability (IIV) in Vd/F, 36% in ke/F, and 24% in Tlag, respectively. Formulation did not affect the variability of any of the pharmacokinetic parameters. Tlag was longer, whereas Vd/F and ke/F were lower in aged compared to adult animals; in female aged dogs ke/F was lower than in male aged dogs; however, the differences were of low magnitude. Different disposition of cephalexin may be expected in aged dogs.

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Section: Discussionsupporting

confidence: 60%

A Population Pharmacokinetic Approach to Describe Cephalexin Disposition in Adult and Aged Dogs

Prados

Schaiquevich

Kreil

et al. 2014

Veterinary Medicine International

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“…For example, Nielsen et al (37) found that treatment of the basolateral membrane with insulin increased Gly-Sar uptake in Caco-2 cells. Addition of leptin to the apical membrane of Caco-2 cells or mouse jejunum was shown to increase cephalexin and Gly-Sar transport through increases in membrane PepT1 and reduction of intracellular quantities of the protein (21). Stimulation of peptide transport by insulin or leptin is thought to involve increased trafficking of the cytoplasmic pool of PepT1 to the apical membrane.…”

Section: Discussionmentioning

confidence: 99%

“…The transport capacity of PepT1 in the small intestine was evaluated using the in situ single-pass jejunal perfusion technique, as previously described (21,22). Briefly, an inflow cannula made of silastic tube (1.65-mm o.d., 0.76-mm i.d., 10-cm length) was inserted into the jejunum~1 cm below the ligament of Treitz and an outflow cannula was set up at a distance of 10 cm.…”

Section: Methodsmentioning

confidence: 99%

Lactobacillus plantarum Consumption Increases PepT1-Mediated Amino Acid Absorption by Enhancing Protein Kinase C Activity in Spontaneously Colitic Mice

Chen¹,

Shen²,

Zhou³

et al. 2010

The Journal of Nutrition

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Although probiotic consumption has generally been shown to have many beneficial effects for the prevention and treatment of inflammatory bowel disease, the effects of Lactobacillus plantarum (LP) on intestinal nutrient absorption, particularly oligopeptide transporter 1 (PepT1)-mediated absorption of dietary protein under inflammatory conditions, has not yet been characterized. In this study, we first investigated the effects of LP consumption on plasma amino acid concentrations and PepT1-mediated absorption of cephalexin in the small intestine of wild-type (WT) mice and interleukin-10 knockout (IL-10(-/-)) mice, a model of spontaneous colitis. We then analyzed expression and distribution of PepT1 and protein kinase C (PKC) activity in the jejunum of these mice. LP consumption (10(9) colony-forming units/0.5 mL) delivered by gavage once per day for 4 wk increased the total plasma amino acid concentration and the concentration of plasma cephalexin through enhancement of PepT1-mediated uptake in LP treated IL-10(-/-) mice compared with IL-10(-/-) mice. However, Western blotting and quantitative PCR analysis revealed no significant differences in PepT1 protein and mRNA expression between LP-treated and untreated mice. Additionally, immunofluorescence analysis showed that PepT1 did not appear to be mislocalized in IL-10(-/-) mice. Interestingly, IL-10(-/-) mice had significantly lower PKC activity and expression of phosphorylated PKC compared with WT mice, and these decreases could be prevented by LP treatment. These data suggest that consumption of LP enhances PepT1-mediated amino acid absorption, likely through alterations in PKC activity, as opposed to changes in expression or distribution of PepT1 in the small intestine of IL-10(-/-) mice.

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“…We devised a study using Caco-2 cells and the model dipeptide glycyl-sarcosine (gly-sar). The Caco-2 cell line is a well-characterized, human-derived, cell culture model of intestinal epithelium known to express PepT1; Caco-2 cells are used frequently in studies of nutrient absorption and pharmacokinetics (1-3, 6, 14, 15, 20-22, 24-28, 30-32). Gly-Sar is a model, hydrolysis-resistant dipeptide not found in nature and is used frequently as a substrate to study PepT1-mediated transport (13).…”

Section: Introductionmentioning

confidence: 99%

Differentiating Passive from Transporter-Mediated Uptake by PepT1: A Comparison and Evaluation of Four Methods

Scow

Madhavan

Chaudhry

et al. 2011

Journal of Surgical Research

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Introduction-To quantify transmembrane transport of dipeptides by PepT1, passive uptake (non-PepT1 mediated) must be subtracted from total (measured) uptake. Three methods have been described to estimate passive uptake: perform experiments at cold temperatures, inhibit target dipeptide uptake with greater concentration of a second dipeptide, or use modified MichaelisMenten kinetics. We hypothesized that performing uptake experiments at pH (8.0) would estimate passive uptake accurately, because PepT1 requires a proton gradient. Our aim was to determine the most accurate method to estimate passive uptake.

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PepT1-mediated epithelial transport of dipeptides and cephalexin is enhanced by luminal leptin in the small intestine

Cited by 40 publications

References 52 publications

A Population Pharmacokinetic Approach to Describe Cephalexin Disposition in Adult and Aged Dogs

A Population Pharmacokinetic Approach to Describe Cephalexin Disposition in Adult and Aged Dogs

Lactobacillus plantarum Consumption Increases PepT1-Mediated Amino Acid Absorption by Enhancing Protein Kinase C Activity in Spontaneously Colitic Mice

Differentiating Passive from Transporter-Mediated Uptake by PepT1: A Comparison and Evaluation of Four Methods

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