Preclinical pharmacokinetic studies of the tritium labelled D-enantiomeric peptide D3 developed for the treatment of Alzheimer's disease

Nan Jiang, Leonie H.E. Leithold, Julia Post, Tamar Ziehm, Jörg Mauler, Lothar Gremer, Markus Cremer, Elena Schartmann, N. Jon Shah, Janine Kutzsche, Karl Josef Langen, Jörg Breitkreutz, Dieter Willbold, Antje Willuweit

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Targeting toxic amyloid beta (Aβ) oligomers is currently a very attractive drug development strategy for treatment of Alzheimer's disease. Using mirror-image phage display against Aβ1-42, we have previously identified the fully D-enantiomeric peptide D3, which is able to eliminate Aβ oligomers and has proven therapeutic potential in transgenic Alzheimer's disease animal models. However, there is little information on the pharmacokinetic behaviour of D-enantiomeric peptides in general. Therefore, we conducted experiments with the tritium labelled D-peptide D3 (3H-D3) in mice with different administration routes to study its distribution in liver, kidney, brain, plasma and gastrointestinal tract, as well as its bioavailability by i.p. and p.o. administration. In addition, we investigated the metabolic stability in liver microsomes, mouse plasma, brain, liver and kidney homogenates, and estimated the plasma protein binding. Based on its high stability and long biological half-life, our pharmacokinetic results support the therapeutic potential of D-peptides in general, with D3 being a new promising drug candidate for Alzheimer's disease treatment.

Original languageEnglish
Article numbere0128553
Number of pages15
JournalPLoS ONE
Issue number6
Publication statusPublished - 5 Jun 2015
Externally publishedYes

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