Pharmacokinetic Properties of a Novel d-Peptide Developed to be Therapeutically Active Against Toxic β-Amyloid Oligomers
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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.
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.
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.
These excellent pharmacokinetic properties confirm that RD2 is a very promising drug candidate for AD.
KEY WORDSAlzheimer’s disease d-enantiomer peptide pharmacokinetics preclinical
Relative injected dose
Area under the concentration-time curve
Area under the moment curve
Disintegrations per minute
Human serum albumin
Mean absorption time
Mean residence time
per os, oral delivery
Thin layer chromatography
Distribution volume in steady state
Terminal distribution volume
Terminal elimination rate constant
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.
- 6.DaRocha-Souto B, Scotton TC, Coma M, Serrano-Pozo A, Hashimoto T, Serenó L, et al. Brain oligomeric beta-amyloid but not total amyloid plaque burden correlates with neuronal loss and astrocyte inflammatory response in amyloid precursor protein/tau transgenic mice. J Neuropathol Exp Neurol. 2011;70(5):360–76.PubMedCentralCrossRefPubMedGoogle Scholar
- 7.Decker H, Lo KY, Unger SM, Ferreira ST, Silverman MA. Amyloid-beta peptide oligomers disrupt axonal transport through an NMDA receptor-dependent mechanism that is mediated by glycogen synthase kinase 3 beta in primary cultured hippocampal neurons. J Neurosci. 2010;30(27):9166–71.CrossRefPubMedGoogle Scholar