Yoshino Yuta, Yuan Bo, Miyashita Shin-ich, Iriyama Noriyoshi, Horikoshi Akira, Shikino Osamu, Toyoda Hiroo, Kaise Toshikazu
Department of Clinical Molecular Genetics, Faculty of Pharmacy, Tokyo University of Pharmacy & Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
Anal Bioanal Chem. 2009 Jan;393(2):689-97. doi: 10.1007/s00216-008-2487-9. Epub 2008 Nov 14.
Arsenic trioxide (As(2)O(3)) has been widely accepted as the second-best choice for the treatment of relapsed and refractory acute promyelocytic leukemia (APL) patients. However, a few studies have been conducted on a detailed speciation of As(2)O(3) metabolites in blood samples of patients. To clarify the speciation of arsenic, the blood samples were collected at various time points from a patient with APL after remission induction therapy and during consolidation therapy. The total amounts of arsenic in blood cells and plasma, and the plasma concentrations of inorganic arsenic and methylated metabolites were determined by inductively coupled plasma mass spectrometry (ICP-MS) and high-performance liquid chromatography/ICP-MS, respectively. The total amounts of arsenic in the blood cells were 4-10 times higher than those in plasma. Among all arsenic metabolites, the pentavalent arsenate (As(V)) in plasma was more readily eliminated. During the drug-withdrawal period, the initial plasma concentrations of trivalent arsenic (As(III)) declined more rapidly than those of methylarsonic acid and dimethlyarsinic acid, which are known as the major methylated metabolites of As(III). On the other hand, during the consecutive administration in the consolidation therapy period, the plasma concentrations of total arsenic and arsenic metabolites increased with time. In conclusion, these results may support the idea that methylated metabolites of As(2)O(3) contribute to the efficacy of arsenic in APL patients. These results also suggest that detailed studies on the pharmacokinetics as well as the pharmacodynamics of As(2)O(3) in the blood cells from APL patients should be carried out to provide an effective treatment protocol.
三氧化二砷（As₂O₃）已被广泛认可为复发和难治性急性早幼粒细胞白血病（APL）患者治疗的第二最佳选择。然而，针对患者血样中As₂O₃代谢产物的详细形态分析的研究较少。为了阐明砷的形态，在缓解诱导治疗后及巩固治疗期间的不同时间点，从一名APL患者采集血样。分别采用电感耦合等离子体质谱法（ICP-MS）和高效液相色谱/ICP-MS测定血细胞和血浆中砷的总量，以及无机砷和甲基化代谢产物的血浆浓度。血细胞中砷的总量比血浆中的高4至10倍。在所有砷代谢产物中，血浆中的五价砷酸盐（As(V)）更容易被清除。在停药期间，三价砷（As(III)）的初始血浆浓度下降速度比甲基胂酸和二甲基胂酸更快，这两种物质是As(III)的主要甲基化代谢产物。另一方面，在巩固治疗期间连续给药时，总砷和砷代谢产物的血浆浓度随时间增加。总之，这些结果可能支持As₂O₃的甲基化代谢产物有助于砷对APL患者疗效的观点。这些结果还表明，应开展关于APL患者血细胞中As₂O₃的药代动力学和药效学的详细研究，以提供有效的治疗方案。
