Raghavan K S, Shek E, Bodor N
University of Florida, College of Pharmacy, J. Hillis Miller Health Center, Gainesville 32610.
Anticancer Drug Des. 1987 Aug;2(1):25-36.
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.
一种基于NADH处于平衡态NAD⁺模型的氧化还原化学递送系统被应用于1-(2-氯乙基)-3-环己基-1-亚硝基脲（CCNU）的活性代谢物（D），即CCNU-OH。CCNU-OH的1,4-二氢胡芦巴碱酯，N-(2-氯乙基)-N'-[反式-4-(1,4-二氢-1-甲基-3-吡啶羰氧基)环己基]-N-亚硝基脲（D-CDS），是通过相应的吡啶鎓前体（D-Q⁺）与高活性的1-苄基-1,2-二氢异烟酰胺的直接氢化物转移反应制备的。生物流体中的体外动力学表明D-CDS易于氧化转化为D-Q⁺。一项体内研究表明，向大鼠静脉注射一次D-CDS会导致D-Q⁺在脑中快速蓄积，随后CCNU-OH持续释放，而D-Q⁺则从体循环中快速消除。发现D-Q⁺的脑/血浓度比随时间逐渐增加。在CCNU-OH等摩尔剂量下，发现CCNU-OH的脑/血浓度比接近1。
