In vitro and in vivo evaluations of dihydroquinoline- and dihydroisoquinoline-based targetor moieties for brain-specific chemical delivery systems.
Brain-targeted delivery of various drugs can be successfully achieved by chemical delivery systems (CDS) that contain a 1,4-dihydropyridine-based redox targetor moiety and undergo a sequential metabolism. However, the susceptibility of this moiety toward hydration in acidic media may limit the shelf-life of such compounds in aqueous formulation. Here, a systematic investigation of the chemical stability toward oxidation and hydration of ester and amide derivatives of 3-substituted 1,4-dihydropyridine, 1,4-dihydroquinoline, and 4-substituted 1,2-dihydroisoquinoline is reported, together with the in vitro stability and in vivo (rat) distribution of isoquinoline-based testosterone and hydrocortisone chemical delivery systems, which were selected as having the most suitable acid-resistant targetor moieties.
Bodor
Nicholas
N
Center for Drug Discovery, University of Florida, Health Science Center, Gainesville 32610-0497, USA. nicholas_bodor@ivax.com
Farag
Hassan H
HH
Barros
M Dulce C
MD
Wu
Whei-Mei
WM
Buchwald
Peter
P
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems; D004355:Drug Stability; D005292:Ferricyanides; D006854:Hydrocortisone / Q000008:administration & dosage / Q000493:pharmacokinetics; D006861:Hydrogen Peroxide; D007202:Indicators and Reagents; D007546:Isoquinolines / Q000737:chemistry*; D007700:Kinetics; D008297:Male; D016877:Oxidants; D010084:Oxidation-Reduction; D011804:Quinolines / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012835:Silver Nitrate; D013739:Testosterone / Q000008:administration & dosage / Q000493:pharmacokinetics; D014018:Tissue Distribution
D005292:Ferricyanides; C109853:G 1617; D007202:Indicators and Reagents; D007546:Isoquinolines; D016877:Oxidants; D011804:Quinolines; C007931:hexacyanoferrate III; D013739:Testosterone; D012835:Silver Nitrate; D006861:Hydrogen Peroxide; D006854:Hydrocortisone