Latch Douglas E, Stender Brian L, Packer Jennifer L, Arnold William A, McNeill Kristopher
Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, USA.
Environ Sci Technol. 2003 Aug 1;37(15):3342-50. doi: 10.1021/es0340782.
The photochemical fates of the histamine H2-receptor antagonists cimetidine and ranitidine were studied. Each of the two environmentally relevant pharmaceuticals displayed high rates of reaction with both singlet oxygen (1O2, O2(1delta(g))) and hydroxyl radical (*OH), two transient oxidants formed in sunlit natural waters. For cimetidine, the bimolecular rate constant for reaction with *OH in water is 6.5 +/- 0.5 x 10(9) M(-1) s(-1). Over the pH range 4-10, cimetidine reacts with 1O2 with bimolecular rate constants ranging from 3.3 +/- 0.3 x 10(6) M(-1) s(-1) at low pH to 2.5 +/- 0.2 x 10(8) M(-1) s(-1) in alkaline solutions. The bimolecular rate constants for ranitidine reacting with 1O2 in water ranges from 1.6 +/- 0.2 x 10(7) M(-1) s(-1) at pH 6-6.4 +/- 0.2 x 10(7) M(-1) s(-1) at pH 10. Reaction of ranitidine hydrochloride with *OH proceeds with a rate constant of 1.5 +/- 0.2 x 10(10) M(-1) s(-1). Ranitidine was also degraded in direct photolysis experiments with a half-life of 35 min under noon summertime sunlight at 45 degrees latitude, while cimetidine was shown to be resistant to direct photolysis. The results of these experiments, combined with the expected steady-state near surface concentrations of 1O2 and *OH, indicate that photooxidation mediated by 1O2 is the likely degradation pathway for cimetidine in most natural waters, and photodegradation by direct photolysis is expected to be the major pathway for ranitidine, with some degradation caused by 1O2. These predictions were verified in studies using Mississippi River water. Model compounds were analyzed by laser flash photolysis experiments to assess which functionalities within ranitidine and cimetidine are most susceptible to singlet-oxygenation and direct photolysis. The heterocyclic moieties of the pharmaceuticals were clearly implicated as the sites of reaction with 1O2, as evidenced by the high relative rate constants of the furan and imidazole models. The nitroacetamidine portion of ranitidine has been shown to be the moiety active in direct photolysis.
研究了组胺H2受体拮抗剂西咪替丁和雷尼替丁的光化学归宿。这两种与环境相关的药物中的每一种都与单线态氧（1O2，O2(1δ(g))）和羟基自由基（OH）显示出高反应速率，这两种瞬态氧化剂在阳光照射的天然水中形成。对于西咪替丁，其在水中与OH反应的双分子速率常数为6.5±0.5×10(9) M(-1) s(-1)。在pH值4 - 10范围内，西咪替丁与1O2反应的双分子速率常数范围从低pH值下的3.3±0.3×10(6) M(-1) s(-1)到碱性溶液中的2.5±0.2×10(8) M(-1) s(-1)。雷尼替丁在水中与1O2反应的双分子速率常数在pH 6时为1.6±0.2×10(7) M(-1) s(-1)，在pH 10时为6.4±0.2×10(7) M(-1) s(-1)。盐酸雷尼替丁与OH反应的速率常数为1.5±0.2×10(10) M(-1) s(-1)。在45度纬度夏季中午阳光照射下的直接光解实验中，雷尼替丁也会降解，半衰期为35分钟，而西咪替丁则显示出对直接光解具有抗性。这些实验结果，结合预期的1O2和OH在近表面的稳态浓度，表明在大多数天然水中，由1O2介导的光氧化是西咪替丁可能的降解途径，而直接光解导致的光降解预计是雷尼替丁的主要途径，同时也有一些降解是由1O2引起的。这些预测在使用密西西比河水的研究中得到了验证。通过激光闪光光解实验分析模型化合物，以评估雷尼替丁和西咪替丁中的哪些官能团最易受到单线态氧氧化和直接光解的影响。呋喃和咪唑模型的相对速率常数较高，证明了药物的杂环部分显然是与1O2反应的位点。雷尼替丁的硝基乙脒部分已被证明是直接光解中的活性部分。
