Speciation of arsenic trioxide metabolites in blood cells and plasma of a patient with acute promyelocytic leukemia.
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.
Yoshino
Yuta
Y
Department of Clinical Molecular Genetics, Faculty of Pharmacy, Tokyo University of Pharmacy & Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
Yuan
Bo
B
Miyashita
Shin-ich
SI
Iriyama
Noriyoshi
N
Horikoshi
Akira
A
Shikino
Osamu
O
Toyoda
Hiroo
H
Kaise
Toshikazu
T
D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000097:blood* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000097:blood* / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D010087:Oxides / Q000097:blood* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012008:Recurrence; D012074:Remission Induction; D013997:Time Factors; D014212:Tretinoin / Q000627:therapeutic use
D001152:Arsenicals; D010087:Oxides; D014212:Tretinoin; D000077237:Arsenic Trioxide