TY - JOUR
T1 - Preclinical pharmacokinetic studies of the tritium labelled D-enantiomeric peptide D3 developed for the treatment of Alzheimer's disease
AU - Jiang, Nan
AU - Leithold, Leonie H.E.
AU - Post, Julia
AU - Ziehm, Tamar
AU - Mauler, Jörg
AU - Gremer, Lothar
AU - Cremer, Markus
AU - Schartmann, Elena
AU - Shah, N. Jon
AU - Kutzsche, Janine
AU - Langen, Karl Josef
AU - Breitkreutz, Jörg
AU - Willbold, Dieter
AU - Willuweit, Antje
PY - 2015/6/5
Y1 - 2015/6/5
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84934890778
U2 - 10.1371/journal.pone.0128553
DO - 10.1371/journal.pone.0128553
M3 - Article
C2 - 26046986
AN - SCOPUS:84934890778
SN - 1932-6203
VL - 10
JO - PLoS ONE
JF - PLoS ONE
IS - 6
M1 - e0128553
ER -