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Cancer Chemotherapy and Pharmacology

, Volume 59, Issue 4, pp 485–493 | Cite as

Pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory acute promyelocytic leukemia treated with arsenic trioxide

  • Shinya Fujisawa
  • Ryuzo Ohno
  • Kazuyuki Shigeno
  • Naohi Sahara
  • Satoki Nakamura
  • Kensuke Naito
  • Miki Kobayashi
  • Kaori Shinjo
  • Akihiro Takeshita
  • Yoshinari Suzuki
  • Hisakuni Hashimoto
  • Kenji Kinoshita
  • Masahito Shimoya
  • Toshikazu Kaise
  • Kazunori Ohnishi
Original Article

Abstract

Purpose

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 (MAAV) and dimethylarsinic acid (DMAAV) 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 AUC0–∞ 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 MAAV and DMAAV 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 day1 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.

Keywords

Arsenic Inductivity Couple Plasma Mass Spectrometry Acute Promyelocytic Leukemia Repeated Administration Arsenic Species 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We thank Mr. Masaya Tajima and Dr. Hideya Mukai from Nippon Shinyaku Co. Ltd. for their help in preparing this article.

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Shinya Fujisawa
    • 1
  • Ryuzo Ohno
    • 2
  • Kazuyuki Shigeno
    • 1
  • Naohi Sahara
    • 1
  • Satoki Nakamura
    • 1
  • Kensuke Naito
    • 1
  • Miki Kobayashi
    • 1
  • Kaori Shinjo
    • 1
  • Akihiro Takeshita
    • 3
  • Yoshinari Suzuki
    • 4
  • Hisakuni Hashimoto
    • 4
  • Kenji Kinoshita
    • 5
  • Masahito Shimoya
    • 5
  • Toshikazu Kaise
    • 5
  • Kazunori Ohnishi
    • 1
    • 6
  1. 1.Department of Medicine IIIHamamatsu University School of MedicineHamamatsuJapan
  2. 2.Aichi Cancer Center HospitalNagoya, AichiJapan
  3. 3.Department of Laboratory MedicineHamamatsu University School of MedicineHamamatsuJapan
  4. 4.Pharmacy DepartmentHamamatsu University HospitalHamamatsuJapan
  5. 5.Laboratory of Environmental ChemodynamicsTokyo University of Pharmacy and Life ScienceHachioji, TokyoJapan
  6. 6.Division of Clinical OncologyHamamatsu University School of MedicineHamamatsuJapan

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