Role and Relevance of Pept1 in Drug Absorption, Disposition, and Dynamics

Summary

Principal Investigator: David E Smith
Abstract: DESCRIPTION (provided by applicant): PEPT1, a proton-coupled oligopeptide transporter (POT) of the SLC15 family, has nutritional importance because of its intestinal absorption of small peptides from the diet and because of its reabsorption of peptide-bound amino nitrogen from glomerular filtrate in kidney. PEPT1 also has pharmacological significance in its ability to transport therapeutic agents (e.g., ?-lactam antibiotics, angiotensin-converting enzyme inhibitors, antiviral nucleoside prodrugs) and potentially toxic peptidomimetics (e.g., 5-aminolevulinic acid). However, other members of the POT family (i.e., PEPT2, PHT1 and PHT2) are expressed in the intestine and kidney, thereby confounding an accurate assessment of its role and relevance. Our laboratory has recently established a colony of PEPT1 knockout mice, a unique resource in which to validate in situ mechanistic studies with in vivo whole animal experiments. The availability of these knockout mice is particularly exciting given the recent association of aberrant PEPT1 colonic expression and inflammatory bowel disease progression. With this in mind, the long-term objectives of this "resubmission" application are to define the physiological, pharmacological, and pathological roles and relevance of PEPT1. Our working hypothesis is that PEPT1 is a critical transporter in the intestinal absorption, disposition, and dynamics of peptides and peptide-like drugs, and that it plays an important role in the pathogenesis of intestinal inflammation. To test this hypothesis, the following specific aims are proposed: Aim 1. To determine the in situ intestinal transport properties of peptide-like drugs (and prodrugs), bacterially-derived peptides, and anti- inflammatory tripeptides;Aim 2. To characterize the in vivo absorption and disposition of peptide-like drugs (and prodrugs), and anti-inflammatory tripeptides;and Aim 3. To evaluate the role and relevance of PEPT1 in mediating the inflammatory response to bacterially-derived peptides and anti-inflammatory tripeptides. By combining cellular/tissue, molecular, and whole animal studies in wild-type and PEPT1 null mice, the proposed studies will greatly advance our understanding of the in vivo role, significance and vectorial transport of peptides, peptide-like drugs (and prodrugs) by PEPT1 (as opposed to other transporters and/or passive processes). Moreover, our findings will provide important new insights into the mechanisms of PEPT1- mediated intestinal inflammation and, as a result, identify a new target for therapeutic strategies against inflammatory bowel disease. Finally, the proposed studies may offer rare insight into the variability of peptide/mimetic kinetics and response in those human subjects with genetic polymorphisms.
Funding Period: 1988-02-01 - 2014-05-31
more information: NIH RePORT

Top Publications

  1. ncbi Role of PEPT2 in glycylsarcosine transport in astrocyte and glioma cultures
    Jianming Xiang
    Department of Neurosurgery, University of Michigan, 1500 East Medical Center Drive, R5550 Kresge I, Ann Arbor, 48109 0532, USA
    Neurosci Lett 396:225-9. 2006
  2. pmc Effect of dose escalation on the in vivo oral absorption and disposition of glycylsarcosine in wild-type and Pept1 knockout mice
    Dilara Jappar
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
    Drug Metab Dispos 39:2250-7. 2011
  3. pmc Influence of fed-fasted state on intestinal PEPT1 expression and in vivo pharmacokinetics of glycylsarcosine in wild-type and Pept1 knockout mice
    Ke Ma
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
    Pharm Res 29:535-45. 2012
  4. pmc Choroid plexus transport: gene deletion studies
    Richard F Keep
    Department of Neurosurgery, R5018 BSRB, University of Michigan, Ann Arbor, Michigan 48109 2200, USA
    Fluids Barriers CNS 8:26. 2011
  5. pmc Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance
    Jingfeng Li
    Human Cancer Genetics Program and Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
    Genome Res 22:870-84. 2012
  6. pmc Species-dependent uptake of glycylsarcosine but not oseltamivir in Pichia pastoris expressing the rat, mouse, and human intestinal peptide transporter PEPT1
    Yongjun Hu
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 4742C Medical Sciences II, 1150 W Medical Center Dr, Ann Arbor, MI 48109 5633, USA
    Drug Metab Dispos 40:1328-35. 2012
  7. pmc Role of the intestinal peptide transporter PEPT1 in oseltamivir absorption: in vitro and in vivo studies
    Agnès Poirier
    Non Clinical Safety, F Hoffmann La Roche Ltd, Grenzacherstrasse 124, CH 4070, Basel, Switzerland
    Drug Metab Dispos 40:1556-65. 2012
  8. pmc Relevance of PepT1 in the intestinal permeability and oral absorption of cefadroxil
    Maria M Posada
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109 5633, USA
    Pharm Res 30:1017-25. 2013
  9. pmc Impact of intestinal PepT1 on the kinetics and dynamics of N-formyl-methionyl-leucyl-phenylalanine, a bacterially-produced chemotactic peptide
    Shu Pei Wu
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
    Mol Pharm 10:677-84. 2013
  10. pmc Significance of peptide transporter 1 in the intestinal permeability of valacyclovir in wild-type and PepT1 knockout mice
    Bei Yang
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 1150 W Medical Center Drive, 4742C Medical Sciences II, Ann Arbor, MI 48109 5633, USA
    Drug Metab Dispos 41:608-14. 2013

Research Grants

Detail Information

Publications34

  1. ncbi Role of PEPT2 in glycylsarcosine transport in astrocyte and glioma cultures
    Jianming Xiang
    Department of Neurosurgery, University of Michigan, 1500 East Medical Center Drive, R5550 Kresge I, Ann Arbor, 48109 0532, USA
    Neurosci Lett 396:225-9. 2006
    ..These results indicate that PEPT2 is the sole transporter involved in the uptake of GlySar into neonatal cultured astrocytes. However, PEPT2 mRNA appears to be absent from two glioma cell lines...
  2. pmc Effect of dose escalation on the in vivo oral absorption and disposition of glycylsarcosine in wild-type and Pept1 knockout mice
    Dilara Jappar
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
    Drug Metab Dispos 39:2250-7. 2011
    ..The AUC of GlySar was proportional to dose in both genotypes over 1 to 100 nmol/g, with minor decrements at the two highest doses...
  3. pmc Influence of fed-fasted state on intestinal PEPT1 expression and in vivo pharmacokinetics of glycylsarcosine in wild-type and Pept1 knockout mice
    Ke Ma
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
    Pharm Res 29:535-45. 2012
    ..To determine if fasting would affect the intestinal expression and in vivo functional activity of PEPT1 as determined after oral dosing of the dipeptide glycylsarcosine (GlySar)...
  4. pmc Choroid plexus transport: gene deletion studies
    Richard F Keep
    Department of Neurosurgery, R5018 BSRB, University of Michigan, Ann Arbor, Michigan 48109 2200, USA
    Fluids Barriers CNS 8:26. 2011
    ..It also discusses the pros and cons of using KO animals in such studies and the technical approaches that can be used...
  5. pmc Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance
    Jingfeng Li
    Human Cancer Genetics Program and Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
    Genome Res 22:870-84. 2012
    ..This study defines an unexpectedly strong functional impact of ERVs in disrupting gene transcription at a distance and demonstrates that ongoing retrotransposition can contribute significantly to natural phenotypic diversity...
  6. pmc Species-dependent uptake of glycylsarcosine but not oseltamivir in Pichia pastoris expressing the rat, mouse, and human intestinal peptide transporter PEPT1
    Yongjun Hu
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 4742C Medical Sciences II, 1150 W Medical Center Dr, Ann Arbor, MI 48109 5633, USA
    Drug Metab Dispos 40:1328-35. 2012
    ..Finally, the mouse appeared to be a better animal model than the rat for exploring the intestinal absorption and pharmacokinetics of peptides and peptide-like drugs in human...
  7. pmc Role of the intestinal peptide transporter PEPT1 in oseltamivir absorption: in vitro and in vivo studies
    Agnès Poirier
    Non Clinical Safety, F Hoffmann La Roche Ltd, Grenzacherstrasse 124, CH 4070, Basel, Switzerland
    Drug Metab Dispos 40:1556-65. 2012
    ..This change has no clinical implications. Taken together, the results do not implicate either rat Pept1 or hPEPT1 in the oral absorption of oseltamivir...
  8. pmc Relevance of PepT1 in the intestinal permeability and oral absorption of cefadroxil
    Maria M Posada
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109 5633, USA
    Pharm Res 30:1017-25. 2013
    ..To determine the contribution of intestinal PepT1 on the permeability and oral absorption of the β-lactam antibiotic drug cefadroxil...
  9. pmc Impact of intestinal PepT1 on the kinetics and dynamics of N-formyl-methionyl-leucyl-phenylalanine, a bacterially-produced chemotactic peptide
    Shu Pei Wu
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
    Mol Pharm 10:677-84. 2013
    ..In conclusion, these findings demonstrated that PepT1 had a major influence on the permeability of fMet-Leu-Phe in duodenum, jejunum, and ileum in wild-type mice and on inflammatory response in intestinal regions that expressed PepT1...
  10. pmc Significance of peptide transporter 1 in the intestinal permeability of valacyclovir in wild-type and PepT1 knockout mice
    Bei Yang
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 1150 W Medical Center Drive, 4742C Medical Sciences II, Ann Arbor, MI 48109 5633, USA
    Drug Metab Dispos 41:608-14. 2013
    ..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...
  11. pmc Corticosterone mediates stress-related increased intestinal permeability in a region-specific manner
    G Zheng
    Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
    Neurogastroenterol Motil 25:e127-39. 2013
    ..It is unknown whether corticosterone (CORT) plays a role in mediating alterations of epithelial permeability in response to CPS...
  12. pmc Importance of Peptide transporter 2 on the cerebrospinal fluid efflux kinetics of glycylsarcosine characterized by nonlinear mixed effects modeling
    Yeamin Huh
    Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109, USA
    Pharm Res 30:1423-34. 2013
    ..To develop a population pharmacokinetic model to quantitate the distribution kinetics of glycylsarcosine (GlySar), a substrate of peptide transporter 2 (PEPT2), in blood, CSF and kidney in wild-type and PEPT2 knockout mice...
  13. pmc Functional and molecular expression of the proton-coupled oligopeptide transporters in spleen and macrophages from mouse and human
    Dongli Sun
    College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P R China
    Mol Pharm 10:1409-16. 2013
    ..Moreover, it appears that the PepT2-mediated uptake of γ-iE-DAP and MDP in macrophages further contributes to the innate immune response...
  14. pmc Proton-coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications
    David E Smith
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
    Mol Aspects Med 34:323-36. 2013
    ..Whenever possible, the relevance of drug-drug interactions and regulatory mechanisms are evaluated using in vivo studies...
  15. pmc Impact of peptide transporter 1 on the intestinal absorption and pharmacokinetics of valacyclovir after oral dose escalation in wild-type and PepT1 knockout mice
    Bei Yang
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan
    Drug Metab Dispos 41:1867-74. 2013
    ..Moreover, this study provides definitive evidence for the rational development of a PepT1-targeted prodrug strategy...
  16. pmc Peptide transporter 1 is responsible for intestinal uptake of the dipeptide glycylsarcosine: studies in everted jejunal rings from wild-type and Pept1 null mice
    Katherine Ma
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, USA
    J Pharm Sci 100:767-74. 2011
    ..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...
  17. pmc Significance and regional dependency of peptide transporter (PEPT) 1 in the intestinal permeability of glycylsarcosine: in situ single-pass perfusion studies in wild-type and Pept1 knockout mice
    Dilara Jappar
    University of Michigan, 4742 Medical Sciences II, 1150 W Medical Center Drive, Ann Arbor, MI 48109 5633, USA
    Drug Metab Dispos 38:1740-6. 2010
    ..Our findings suggest that a loss of PEPT1 activity (e.g., due to polymorphisms, disease, or drug interactions) should have a major effect in reducing the intestinal absorption of di-/tripeptides, peptidomimetics, and peptide-like drugs...
  18. pmc PEPT2-mediated transport of 5-aminolevulinic acid and carnosine in astrocytes
    Jianming Xiang
    Department of Neurosurgery, University of Michigan, 5014 BSRB, Ann Arbor, MI 48109 2200, USA
    Brain Res 1122:18-23. 2006
    ..These results demonstrate that PEPT2 is the primary transporter responsible for the astrocytic uptake of ALA and carnosine...
  19. ncbi PEPT1 enhances the uptake of gabapentin via trans-stimulation of b0,+ exchange
    Theresa V Nguyen
    Deparment of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109 1065, USA
    Pharm Res 24:353-60. 2007
    ..The aims of this study were (1) to determine whether amino acid and dipeptide loading can improve the effective permeability of gabapentin and (2) to characterize the underlying mechanism that is responsible for this interaction...
  20. ncbi In vivo effects of glycyl-glutamate and glycyl-sarcosine on gabapentin oral absorption in rat
    Theresa V Nguyen
    Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, Michigan 48109 1065, USA
    Pharm Res 24:1538-43. 2007
    ..The objective of this study was to evaluate the in vivo consequences of glycyl-glutamate coadministration on gabapentin oral absorption...
  21. ncbi Impact of genetic knockout of PEPT2 on cefadroxil pharmacokinetics, renal tubular reabsorption, and brain penetration in mice
    Hong Shen
    Department of Pharmaceutical Sciences, The University of Michigan, Ann Arbor, Michigan, USA
    Drug Metab Dispos 35:1209-16. 2007
    ..These findings demonstrate that renal PEPT2 is almost entirely responsible for the reabsorption of cefadroxil in kidney and that choroid plexus PEPT2 limits the exposure of cefadroxil (and perhaps other aminocephalosporins) in CSF...
  22. ncbi Peptide transporter 2 (PEPT2) expression in brain protects against 5-aminolevulinic acid neurotoxicity
    Yongjun Hu
    Department of Pharmaceutical Sciences and Upjohn Center for Clinical Pharmacology, The University of Michigan, Ann Arbor, Michigan, USA
    J Neurochem 103:2058-65. 2007
    ....
  23. pmc Role and relevance of PEPT2 in drug disposition, dynamics, and toxicity
    Mohamed A Kamal
    Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109 5633, USA
    Drug Metab Pharmacokinet 23:236-42. 2008
    ..In the case of 5-aminolevulinic acid, such regional modulation of drug disposition translates directly into significant changes in neurotoxicity...
  24. pmc Transport mechanisms of carnosine in SKPT cells: contribution of apical and basolateral membrane transporters
    Dilara Jappar
    Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109, USA
    Pharm Res 26:172-81. 2009
    ....
  25. pmc Influence of genetic knockout of Pept2 on the in vivo disposition of endogenous and exogenous carnosine in wild-type and Pept2 null mice
    Mohamed A Kamal
    Univeersity of Michigan, Upjohn Center for Clinical Pharmacology, Ann Arbor, Michigan 48109 5633, USA
    Am J Physiol Regul Integr Comp Physiol 296:R986-91. 2009
    ..However, endogenous carnosine levels may be under homeostatic control to maintain systemic and central concentrations under physiological in vivo conditions...
  26. pmc Clathrin- and dynamin-dependent endocytic pathway regulates muramyl dipeptide internalization and NOD2 activation
    Noemi Marina-Garcia
    Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, 48109, USA
    J Immunol 182:4321-7. 2009
    ..These studies provide evidence for a clathrin- and dynamin-dependent endocytosis pathway that mediates MDP uptake and NOD2 activation...
  27. pmc Enhanced antinociceptive response to intracerebroventricular kyotorphin in Pept2 null mice
    Huidi Jiang
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, USA
    J Neurochem 109:1536-43. 2009
    ....
  28. pmc Targeted disruption of peptide transporter Pept1 gene in mice significantly reduces dipeptide absorption in intestine
    Yongun Hu
    Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109, USA
    Mol Pharm 5:1122-30. 2008
    ..These novel findings provide strong evidence that PEPT1 has a major role in the in vivo oral absorption of dipeptides...
  29. pmc Pharmacodynamic differentiation of lorazepam sleepiness and dizziness using an ordered categorical measure
    Mohamed A Kamal
    F Hoffmann La Roche Inc, Modeling and Simulation, Nutley, NJ 07110, USA
    J Pharm Sci 99:3628-41. 2010
    ..The higher intensity of sleepiness may be directly related to baseline (no drug present) while the increase in intensity as a result of drug was relatively similar for both AEs...
  30. pmc Kyotorphin transport and metabolism in rat and mouse neonatal astrocytes
    Jianming Xiang
    Department of Neurosurgery, Medical School, University of Michigan, Ann Arbor, Michigan, USA
    Brain Res 1347:11-8. 2010
    ..These processes occur at similar rates and may be linked. This supports the contention that oligopeptide transport may have an impact on the extracellular clearance (and potentially activity) of certain neuropeptides...
  31. pmc Distribution of glycylsarcosine and cefadroxil among cerebrospinal fluid, choroid plexus, and brain parenchyma after intracerebroventricular injection is markedly different between wild-type and Pept2 null mice
    David E Smith
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109 5633, USA
    J Cereb Blood Flow Metab 31:250-61. 2011
    ..These studies show that PEPT2 knockout can significantly modify the spatial distribution of GlySar and cefadroxil (and presumably other peptides/mimetics and peptide-like drugs) in brain...
  32. pmc Impact of lipopolysaccharide-induced inflammation on the disposition of the aminocephalosporin cefadroxil
    Yeamin Huh
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
    Antimicrob Agents Chemother 57:6171-8. 2013
    ....

Research Grants30

  1. Mucosal Cell Transporters and Enzymes for Enhancing Oral Drug Absorption
    Gordon L Amidon; Fiscal Year: 2013
    ..This will enable the development of new, more effective, drugs for treatment of viral infections. ..
  2. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  3. BEHAVIORAL GENOMICS OF ALCOHOL NEUROADAPTATION
    John C Crabbe; Fiscal Year: 2013
    ..An Education and Outreach component trains pre- and post-doctoral students in alcohol research, disseminates research findings to the public, and engages in a range of activities with elementary-to-high school students. ..
  4. Endogenous Cannabinoids and Brain Function
    Aron H Lichtman; Fiscal Year: 2013
    ..Ultimately, the knowledge gained from this basic research will yield novel therapeutic targets that can be exploited with the pharmacological agents developed here. PROGRAM CHARACTERISTICS ..
  5. Ether Lipids, Elcosanoids, and Lung Cell Pathophysiology
    CHRISTINA CARROLL LESLIE; Fiscal Year: 2013
    ..By using multidisciplinary approaches, we will determine the structural identity of lipid mediators, the molecular mechanisms involved in their production and how they function to regulate lung responses. ..
  6. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  7. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..
  8. Broad Spectrum Antiviral Nucleoside Phosphonate Analogs
    John M Hilfinger; Fiscal Year: 2013
    ..John Hilfinger at TSRL, Inc. and Professor Charles McKenna at the University of Southern California and includes Professor Mark Prichard at the University of Alabama at Birmingham as the participating virologist. ..
  9. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
    ..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..
  10. NanoART Manufacture, Delivery and Pharmacokinetics for Optimizing Drug Adherence
    Howard E Gendelman; Fiscal Year: 2013
    ..Third, animal studies will be performed in virus-infected rhesus macaques infected with recombinant lentivirus hybrids of SIV and HIV (SHIV) for safety and efficacy investigations, respectively. ..
  11. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  12. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..