Veszelovsky E, Holford N H, Thomsen L L, Knowles R G, Baguley B C
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Cancer Chemother Pharmacol. 1995;36(2):155-9. doi: 10.1007/BF00689201.
Nitric oxide (NO) is produced in mammals by the enzyme NO synthase (NOS) in response to a number of agents, including the experimental antitumour agent flavone acetic acid (FAA) and the cytokine tumour necrosis factor-alpha (TNF). NO is converted rapidly in the presence of oxygen, water and haemoglobin to oxidation products, largely nitrate. To quantitate the production of nitric oxide it is necessary to know the clearance of nitrate. The concentration of nitrite and nitrate ion in the plasma of C3H and BDF1 (C57BL6 x DBA2) mice was assessed before and after injection of sodium nitrate and sodium nitrite. Nitrite was covered rapidly to nitrate and the kinetics of elimination of nitrate were determined. There was no significant difference between results obtained with different mouse strains, between levels of nitrite and nitrate, or between i.p. and i.v. administration, and the observations were therefore combined. The volume of distribution of nitrate was 0.71 +/- 0.04 l/kg and the clearance was 0.32 +/- 0.02 l/h-1/kg-1 (plasma half-life, 1.54 h). Using previously published data, we developed a pharmacokinetic-pharmacodynamic model that relates the production of TNF in response to administration of FAA, the enhancement of NOS activity in response to TNF, and the elevation of plasma nitrate in response to NO production. This information permits the prediction from observed plasma nitrate values of the amount of NOS induced in vivo.
在哺乳动物中，一氧化氮（NO）由一氧化氮合酶（NOS）产生，以响应多种因子，包括实验性抗肿瘤药物黄酮乙酸（FAA）和细胞因子肿瘤坏死因子-α（TNF）。在氧气、水和血红蛋白存在的情况下，NO会迅速转化为氧化产物，主要是硝酸盐。为了定量一氧化氮的产生，有必要了解硝酸盐的清除率。在注射硝酸钠和亚硝酸钠之前和之后，评估了C3H和BDF1（C57BL6×DBA2）小鼠血浆中亚硝酸盐和硝酸根离子的浓度。亚硝酸盐迅速转化为硝酸盐，并测定了硝酸盐的消除动力学。不同小鼠品系、亚硝酸盐和硝酸盐水平之间，以及腹腔注射和静脉注射之间的结果没有显著差异，因此将观察结果合并。硝酸盐的分布容积为0.71±0.04 l/kg，清除率为0.32±0.02 l/h-1/kg-1（血浆半衰期，1.54 h）。利用先前发表的数据，我们建立了一个药代动力学-药效学模型，该模型将FAA给药后TNF的产生、TNF作用下NOS活性的增强以及NO产生后血浆硝酸盐的升高联系起来。这些信息使得能够根据观察到的血浆硝酸盐值预测体内诱导的NOS量。
