Journalartikel

Jahr der Veröffentlichung: 2015

Seiten: 417-424

Zeitschrift: Journal of Pharmaceutical and Biomedical Analysis

Bandnummer: 102

ISSN: 0731-7085

DOI Link: https://doi.org/10.1016/j.jpba.2014.10.001

Verlag: Elsevier

Abstract: 
Alzheimer's disease (AD) is the most common cause of dementia. Since no causative treatment is available, new therapeutic options are utmost needed. Several pirinixic acid derivatives, including MH84 (2-((4,6-bis(4-(trifluoromethyl)phenethoxy)pyrimidin-2-yl)thio)hexanoic acid), have shown promising in vitro results as gamma-secretase modulators as well as PPAR gamma activators as potential pharmacological compounds against AD.Using a newly developed and validated sensitive LC-MS (APCI-qTOF mass analyzer) method, the pharmacokinetic and long-term accumulating properties as well as the blood-brain-barrier permeability of MH84 were evaluated in a preclinical animal study. MH84 was administered to mice by oral gavage with a dose of 12 mg/kg. Nine time points from 0.5 to 48 h with 6 animals per point were investigated. Additionally 6 animals were fed daily, for 21 days with an identical dose to determine possible long-term accumulation in plasma and brain tissue.The sample preparation was performed by a liquid-liquid extraction on Extrelut(R) columns whereas the LC separation was operated on a MulthoHigh 100 RP 18-5 mu column (125 x 4 mm) using an isocratic mobile phase of formic acid (0.1% (v/v))-methanol mixture (11:89 (v/v)) at a flow rate of 1 ml/min. The validation confirmed the new LC-MS method to be precise, accurate and reliable. After oral application, C-max and T-max of unmetabolized MH84 was determined to be 10.90 mu g/ml and 3 h in plasma. In brain tissue a constant level of 300 to maximum 320.64 ng/g was found after 1.5-6 h. Daily gavage for 21 days did not lead to a long-term drug accumulation in the brain. The efficacy of the obtained MH84 levels needs to be investigated in further preclinical pharmacodynamic animal studies. (C) 2014 Elsevier B.V. All rights reserved.

Harvard-Zitierstil: Pellowska, M., Stein, C., Pohland, M., Merk, D., Klein, J., Eckert, G., et al. (2015) Pharmacokinetic properties of MH84, a gamma-secretase modulator with PPAR gamma agonistic activity, Journal of Pharmaceutical and Biomedical Analysis, 102, pp. 417-424. https://doi.org/10.1016/j.jpba.2014.10.001

APA-Zitierstil: Pellowska, M., Stein, C., Pohland, M., Merk, D., Klein, J., Eckert, G., Schubert-Zsilavecz, M., & Wurglics, M. (2015). Pharmacokinetic properties of MH84, a gamma-secretase modulator with PPAR gamma agonistic activity. Journal of Pharmaceutical and Biomedical Analysis. 102, 417-424. https://doi.org/10.1016/j.jpba.2014.10.001