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Pharmaceutical Research

, Volume 33, Issue 2, pp 328–336 | Cite as

Pharmacokinetic Properties of a Novel d-Peptide Developed to be Therapeutically Active Against Toxic β-Amyloid Oligomers

  • Leonie H. E. Leithold
  • Nan Jiang
  • Julia Post
  • Tamar Ziehm
  • Elena Schartmann
  • Janine Kutzsche
  • N. Jon Shah
  • Jörg Breitkreutz
  • Karl-Josef Langen
  • Antje WilluweitEmail author
  • Dieter WillboldEmail author
Research Paper

Abstract

Purpose

It has been shown that amyloid β (Aβ) oligomers play an important role in the pathology of Alzheimer’s disease (AD). D3, a peptide consisting solely of d-enantiomeric amino acid residues, was developed to specifically eliminate Aβ oligomers and is therapeutically active in transgenic AD mice. d-peptides have several advantages over l-peptides, but little is known about their pharmacokinetic potential in vivo. Here, we analysed the pharmacokinetic properties of RD2, a rationally designed and potent D3 derivative.

Methods

The pharmacokinetic analysis was performed using 3H-RD2 after administration via several routes in mice. The time dependent amount of radiolabelled RD2 was measured in plasma and several organ homogenates by liquid scintillation counting. Furthermore, binding to plasma proteins was estimated.

Results

RD2 penetrates into the brain, where it is thought to implement its therapeutic function. All administration routes result in a maximal brain concentration per dose (Cmax/D) of 0.06 (μg/g)/(mg/kg) with brain/plasma ratios ranging between 0.7 and 1.0. RD2 shows a small elimination constant and a long terminal half-life in plasma of more than 2 days. It also exhibits high bioavailability after i.p., s.c. or p.o. administration.

Conclusions

These excellent pharmacokinetic properties confirm that RD2 is a very promising drug candidate for AD.

KEY WORDS

Alzheimer’s disease d-enantiomer peptide pharmacokinetics preclinical 

ABBREVIATIONS

%ID

Relative injected dose

AD

Alzheimer’s disease

AGP

α1-acid glycoprotein

AUC

Area under the concentration-time curve

AUMC

Area under the moment curve

Amyloid β

C

Concentration

Cl

Clearance

D

Dose

dpm

Disintegrations per minute

F

Bioavailability

fu

Unbound fraction

HSA

Human serum albumin

i.p.

Intraperitoneal

i.v.

Intravenous

inf

Infinity

MAT

Mean absorption time

MRT

Mean residence time

n.i.v.

Non-intravenous

p.o.

per os, oral delivery

r2

Correlation coefficient

s.c.

Subcutaneous

t1/2

Terminal half-life

TLC

Thin layer chromatography

Vss

Distribution volume in steady state

Vz

Terminal distribution volume

λz

Terminal elimination rate constant

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

We thank Daniela Schumacher, Elias Bissong and Nicole Niemietz for the excellent technical assistance. Additionally, we thank Jörg Mauler for helping with the data analysis. D.W. was supported by grants from the “Portfolio Technology and Medicine” and the Helmholtz-Validierungsfonds of the Impuls und Vernetzungs-Fonds der Helmholtzgemeinschaft; K.J.L. and D.W. were supported by the “Portfolio Drug Research” of the Impuls und Vernetzungs-Fonds der Helmholtzgemeinschaft. The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Leonie H. E. Leithold
    • 1
  • Nan Jiang
    • 1
  • Julia Post
    • 1
  • Tamar Ziehm
    • 1
  • Elena Schartmann
    • 1
  • Janine Kutzsche
    • 1
  • N. Jon Shah
    • 2
  • Jörg Breitkreutz
    • 3
  • Karl-Josef Langen
    • 2
    • 4
  • Antje Willuweit
    • 2
    Email author
  • Dieter Willbold
    • 1
    • 5
    Email author
  1. 1.Institute of Complex Systems, Structural Biochemistry (ICS-6)Forschungszentrum Jülich GmbHJülichGermany
  2. 2.Institute of Neuroscience and Medicine, Medical Imaging Physics (INM-4)Forschungszentrum Jülich GmbHJülichGermany
  3. 3.Institute of Pharmaceutics and BiopharmaceuticsHeinrich-Heine-Universität DüsseldorfDüsseldorfGermany
  4. 4.Clinic for Nuclear MedicineRWTH Aachen UniversityAachenGermany
  5. 5.Institut für Physikalische BiologieHeinrich-Heine-Universität DüsseldorfDüsseldorfGermany

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