Improved brain delivery of a nonsteroidal anti-inflammatory drug with a synthetic glyceride ester: a preliminary attempt at a CNS drug delivery system for the therapy of Alzheimer's disease

Journal of Drug Targeting
Y DeguchiR Kimura

Abstract

1,3-Diacetyl-2-ketoprofen glyceride (DAKG), a prodrug of ketoprofen, was synthesized as a model compound in our attempt to develop a central nervous system (CNS) drug delivery system to treat Alzheimer's disease. The primary purpose of the present study is to test whether DAKG improves the delivery of ketoprofen to the brain and to quantitatively evaluate several factors that influence the brain distribution of this prodrug. ddY mice were injected with either ketoprofen or DAKG at a dose of 40 micromol/kg and then the plasma and brain pharmacokinetics of these agents were assessed. The brain uptake clearance of ketoprofen and DAKG across the BBB was measured by in situ mouse brain perfusion. In addition, the efflux permeability of ketoprofen through the BBB was evaluated using the in vivo mouse brain microdialysis technique. The in vivo metabolism of DAKG in the brain was assessed by a short infusion into the internal carotid artery coupled with the brain metabolism index (BMI) method. Administration of DAKG produced an approximately 3-fold increase in the area under the brain concentration - time curve of ketoprofen, compared with administration of ketoprofen itself. The brain uptake clearance (CL(in) ) of ketoprofen across th...Continue Reading

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Citations

May 1, 2008·The AAPS Journal·Jarkko RautioJouko Savolainen
Oct 1, 2010·Therapeutic Delivery·V Mangas-SanjuanM Bermejo
Dec 19, 2009·Expert Opinion on Drug Delivery·Santosh Pasha, Kshitij Gupta
Dec 6, 2011·Advanced Drug Delivery Reviews·Devaiah VytlaJames J Chambers
Jan 1, 2005·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Anne MannilaJouko Savolainen
Dec 25, 2004·Drug Metabolism and Pharmacokinetics·Yoshiharu Deguchi
Jan 8, 2014·Bioorganic & Medicinal Chemistry Letters·Helmut M Hügel, Neale Jackson
Jun 19, 2008·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Barbara PavanSilvia Vertuani
May 23, 2006·Pharmaceutical Research·Jagan Mohan R ParepallyQuentin R Smith
Jun 29, 2006·Clinical Pharmacokinetics·Anne MannilaJouko Savolainen
Nov 27, 2020·Drug Delivery·Qiong WuJingjing Sun
Jan 25, 2020·Drug Discovery Today·Saeideh NozohouriThomas J Abbruscato
Dec 22, 2006·Journal of Medicinal Chemistry·Stephen A Hitchcock, Lewis D Pennington

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