Improved delivery through biological membranes. XXX. Synthesis and biological aspects of a 1,4-dihydropyridine based chemical delivery system for brain-sustained delivery of hydroxy CCNU.
A redox chemical delivery system based on the NADH in equilibrium NAD+ model was applied to an active metabolite (D) of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), i.e. CCNU-OH. The 1,4-dihydrotrigonelline ester of CCNU-OH, N-(2-chloro ethyl)-N'-[trans-4-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxy)cyc lohexyl]- N-nitrosourea (D-CDS) was prepared by a direct hydride transfer reaction of the corresponding pyridinium precursor (D-Q+) with a highly reactive 1-benzyl-1,2-dihydroisonicotinamide. The in vitro kinetics in biological fluids indicated facile oxidative conversion of D-CDS to D-Q+. An in vivo study showed that one intravenous injection to rats of D-CDS resulted in rapid brain accumulation of D-Q+, followed by a sustained release of CCNU-OH, while D-Q+ was rapidly eliminated from systemic circulation. The ratio of brain/blood concentration of D-Q+ was found to increase progressively with time. At an equimolar dose of CCNU-OH, the ratio of brain/blood concentration for CCNU-OH was found to be close to unity.
Raghavan
K S
KS
University of Florida, College of Pharmacy, J. Hillis Miller Health Center, Gainesville 32610.
Shek
E
E
Bodor
N
N
D000818:Animals; D001921:Brain / Q000378:metabolism*; D003692:Delayed-Action Preparations; D004095:Dihydropyridines / Q000008:administration & dosage*; D008130:Lomustine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008297:Male; D010084:Oxidation-Reduction; D014677:Pharmaceutical Vehicles / Q000138:chemical synthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D012995:Solubility
D003692:Delayed-Action Preparations; D004095:Dihydropyridines; D014677:Pharmaceutical Vehicles; C040831:4-hydroxylomustine; D008130:Lomustine; C038806:1,4-dihydropyridine