Pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory acute promyelocytic leukemia treated with arsenic trioxide.
OBJECTIVE
To investigate the pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory acute promyelocytic leukemia (APL) treated with arsenic trioxide (ATO) at a daily dose of 0.15 mg/kg.


METHODS
Inorganic arsenic (AsIII and AsV) and the major metabolites monomethylarsonic acid (MAA(V)) and dimethylarsinic acid (DMAA(V)) in plasma and urine collected from 12 Japanese patients were quantified by HPLC/ICP-MS.


RESULTS
The plasma concentrations of AsIII and AsV on day 1 reached the similar Cmax (12.4 +/- 8.4 and 10.2 +/- 3.9 ng/ml) immediately after completion of administration followed by a biphasic elimination. The AUC(0-infinity) of AsV was about twice that of AsIII. The appearance of methylated metabolites in the blood was delayed. During the repeated administration, the plasma concentrations of inorganic arsenic reached the steady state. In contrast, the MAA(V) and DMAA(V) concentrations increased in relation to increased administration frequency. The mean total arsenic excretion rate including inorganic arsenic and methylated arsenic was about 20% of daily dose on day 1 and remained at about 60% of daily dose during week 1-4.


CONCLUSIONS
This study demonstrates that ATO is metabolized when administered intravenously to APL patients and methylated metabolites are promptly eliminated from the blood and excreted into urine after completion of administration, indicating no measurable accumulation of ATO in the blood.
Fujisawa
Shinya
S
Department of Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Ohno
Ryuzo
R
Shigeno
Kazuyuki
K
Sahara
Naohi
N
Nakamura
Satoki
S
Naito
Kensuke
K
Kobayashi
Miki
M
Shinjo
Kaori
K
Takeshita
Akihiro
A
Suzuki
Yoshinari
Y
Hashimoto
Hisakuni
H
Kinoshita
Kenji
K
Shimoya
Masahito
M
Kaise
Toshikazu
T
Ohnishi
Kazunori
K
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001151:Arsenic / Q000493:pharmacokinetics*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010087:Oxides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011446:Prospective Studies
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D001151:Arsenic; D000077237:Arsenic Trioxide