Pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory acute promyelocytic leukemia treated with arsenic trioxide
- 242 Downloads
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.
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.
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.
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.
KeywordsArsenic Inductivity Couple Plasma Mass Spectrometry Acute Promyelocytic Leukemia Repeated Administration Arsenic Species
We thank Mr. Masaya Tajima and Dr. Hideya Mukai from Nippon Shinyaku Co. Ltd. for their help in preparing this article.
- 1.Sun HD, Ma L, Hu XC, Zhang TD (1992) Ai-Lin I treated 32 cases of acute promyelocytic leukemia. Chin J Integr Chin and West Med 12:170–171Google Scholar
- 2.Zhang P, Wang SY, Hu LH (1996) Arsenic trioxide treated 72 cases of acute promyelocytic leukemia. Chin J Hematol 17:58–62Google Scholar
- 3.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) Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89:3354–3360PubMedGoogle Scholar
- 5.Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, Stone RM, Kalaycio M, Scheinberg DA, Steinherz P, Sievers EL, Coutre S, Dahlberg S, Ellison R, Warrell RP Jr (2001) United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 19:3852–3860PubMedGoogle Scholar
- 6.Ohnishi K, Yoshida H, Shigeno K, Nakamura S, Fujisawa S, Naito K, Shinjo K, Fujita Y, Matsui H, Sahara N, Takeshita A, Satoh H, Terada H, Ohno R (2002) Arsenic trioxide therapy for relapsed or refractory Japanese patients with acute promyelocytic leukemia: need for careful electrocardiogram monitoring. Leukemia 16:617–622PubMedCrossRefGoogle Scholar
- 10.Shen Y, Shen ZX, Yan H, Chen J, Zeng XY, Li JM, Li XS, Wu W, Xiong SM, Zhao WL, Tang W, Wu F, Liu YF, Niu C, Wang ZY, Chen SJ, Chen Z (2001) Studies on the clinical efficacy and pharmacokinetics of low-dose arsenic trioxide in the treatment of relapsed acute promyelocytic leukemia: a comparison with conventional dosage. Leukemia 15:735–741PubMedCrossRefGoogle Scholar
- 11.Raffoux E, Rousselot P, Poupon J, Daniel MT, Cassinat B, Delarue R, Taksin AL, Rea D, Buzyn A, Tibi A, Lebbe G, Cimerman P, Chomienne C, Fermand JP, de The H, Degos L, Hermine O, Dombret H (2003) Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia. J Clin Oncol 21:2326–2334PubMedCrossRefGoogle Scholar
- 12.Rousselot P, Larghero J, Arnulf B, Poupon J, Royer B, Tibi A, Madelaine-Chambrin I, Cimerman P, Chevret S, Hermine O, Dombret H, Claude Brouet J, Paul Fermand J (2004) A clinical and pharmacological study of arsenic trioxide in advanced multiple myeloma patients. Leukemia 18:1518–1521PubMedCrossRefGoogle Scholar
- 16.Fukai Y, Hirata M, Ueno M, Ichikawa N, Kobayashi H, Saitoh H, Sakurai T, Kinoshita K, Kaise T, Ohta S (2006) Clinical pharmacokinetic study of arsenic trioxide in an acute promyelocytic leukemia (APL) patients: speciation of arsenic metabolites in serum and urine. Biol Pharm Bull 29:1022–1027PubMedCrossRefGoogle Scholar