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

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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.

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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

Aβ:

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

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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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Authors and Affiliations

  1. Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich GmbH, 52425, Jülich, Germany

    Leonie H. E. Leithold, Nan Jiang, Julia Post, Tamar Ziehm, Elena Schartmann, Janine Kutzsche & Dieter Willbold

  2. Institute of Neuroscience and Medicine, Medical Imaging Physics (INM-4), Forschungszentrum Jülich GmbH, 52425, Jülich, Germany

    N. Jon Shah, Karl-Josef Langen & Antje Willuweit

  3. Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany

    Jörg Breitkreutz

  4. Clinic for Nuclear Medicine, RWTH Aachen University, Aachen, Germany

    Karl-Josef Langen

  5. Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany

    Dieter Willbold

Authors
  1. Leonie H. E. Leithold
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  2. Nan Jiang
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  3. Julia Post
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  10. Antje Willuweit
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  11. Dieter Willbold
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Corresponding authors

Correspondence to Antje Willuweit or Dieter Willbold.

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Leithold, L.H.E., Jiang, N., Post, J. et al. Pharmacokinetic Properties of a Novel d-Peptide Developed to be Therapeutically Active Against Toxic β-Amyloid Oligomers. Pharm Res 33, 328–336 (2016). https://doi.org/10.1007/s11095-015-1791-2

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  • DOI: https://doi.org/10.1007/s11095-015-1791-2

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