Speciation of arsenic trioxide metabolites in blood cells and plasma of a patient with acute promyelocytic leukemia
- 263 Downloads
Arsenic trioxide (As2O3) 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 As2O3 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 (AsV) in plasma was more readily eliminated. During the drug-withdrawal period, the initial plasma concentrations of trivalent arsenic (AsIII) declined more rapidly than those of methylarsonic acid and dimethlyarsinic acid, which are known as the major methylated metabolites of AsIII. 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 As2O3 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 As2O3 in the blood cells from APL patients should be carried out to provide an effective treatment protocol.
KeywordsAcute promyelocytic leukemia Arsenic trioxide Trisenox Arsenic metabolite High-performance liquid chromatography/inductively coupled plasma mass spectrometry Arsenic speciation
This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology and by the Promotion and Mutual Aid Corporation for Private Schools of Japan. We acknowledge Nippon Shinyaku Co. Ltd. for generous supply of Trisenox®.
- 2.Tong JH, Dong S, Geng JP, Huang W, Wang ZY, Sun GL, Chen SJ, Chen Z, Larsen CJ, Berger R (1992) Oncogene 7:311–316Google Scholar
- 4.Melnick A, Licht JD (1999) Blood 93:3167–3215Google Scholar
- 5.Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH (1999) Blood 93:4131–4143Google Scholar
- 6.Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, Zhu J, Tang W, Sun GL, Yang KQ, Chen Y, Zhou L, Fang ZW, Wang YT, Ma J, Zhang P, Zhang TD, Chen SJ, Chen Z, Wang ZY (1997) Blood 89:3354–3360Google Scholar
- 10.Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, Stone RM, Kalaycio M, Scheinberg DA, Steinherz P, Sievers EL, Coutré S, Dahlberg S, Ellison R, Warrell RP Jr (2001) J Clin Oncol 19:3852–3860Google Scholar
- 17.Chen GQ, Zhou L, Styblo M, Walton F, Jing Y, Weinberg R, Chen Z, Waxman S (2003) Cancer Res 63:1853–1859Google Scholar
- 27.Benramdane L, Accominotti M, Fanton L, Malicier D, Vallon JJ (1999) Clin Chem 45:301–306Google Scholar