Side effects of nitroaromatics used as drugs are often assumed to be caused by incomplete enzymatic reduction of the nitro group. However, photoactivation, although usually not considered as a cause of the toxic effects of nitroaromatics, can play a considerable role. Nifedipine, a nitroaromatic as well, is an important drug used in the treatment of myocardial ischaemia and hypertension. It is extremely sensitive to ultraviolet and visible light up to 450 nm and forms a nitroso derivative in vitro. In the present study it is shown that the nitroso compound is a short-lived intermediate in blood and plasma. It reacts with other constituents to form a stable lactam. In vivo, this lactam proves to be rapidly clear from the blood of rats and is excreted almost quantitatively via the bile. The first photoproduct of nifedipine, nitroso nifedipine, is shown to be converted into the lactam mentioned. Beside the lactam, two other products, which are considered to be derivatives of the lactam, are found. One of these two products is also found in the bile of a rat that was exposed to UVA light after intravenous nifedipine administration. This shows that in an in vivo situation, photoproducts can reach organs other than those exposed to the light. In vitro about 45 to 50% of the original amount of nifedipine is not recovered after exposure of nifedipine to UVA in the presence of bovine serum albumin or after incubation of nitroso nifedipine with bovine serum albumin in the dark. As complex binding of nifedipine of plasma proteins is high, the latter finding may have important implications for the situation in vivo.

译文

用作药物的硝基芳烃的副作用通常被认为是由于硝基的酶促还原不完全引起的。然而,光活化虽然通常不被认为是硝基芳烃毒性作用的原因,但可以发挥相当大的作用。硝苯地平也是一种硝基芳香族化合物,是用于治疗心肌缺血和高血压的重要药物。它对高达450 nm的紫外线和可见光极为敏感,并在体外形成亚硝基衍生物。在本研究中,表明亚硝基化合物是血液和血浆中的短暂中间体。它与其他成分反应形成稳定的内酰胺。在体内,这种内酰胺被证明可以从大鼠的血液中迅速清除,并几乎通过胆汁定量排泄。硝苯地平的第一个光产物硝苯地平被证明转化为提到的内酰胺。除了内酰胺外,还发现了另外两种被认为是内酰胺衍生物的产物。在静脉注射硝苯地平后暴露于UVA光的大鼠胆汁中也发现了这两种产品之一。这表明在体内情况下,光产物可以到达暴露于光的器官以外的器官。在牛血清白蛋白存在下将硝苯地平暴露于UVA后或在黑暗中将硝苯地平与牛血清白蛋白孵育后,在体外未回收约45至50% 的原始量的硝苯地平。由于血浆蛋白中硝苯地平的复杂结合很高,后者的发现可能对体内情况具有重要意义。

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