三氧化砷治療之慢性心臟毒性：著重於病理變化、組織砷化合物之分佈及停藥後組織沉積與心臟毒性之可逆性研究
Date Issued
2004
Date
2004
Author(s)
吳美環
DOI
922314B002203
Abstract
Parenteral administration of As2O3 has
recently been recognized as an effective
antineoplastic therapy, especially for the
treatment of acute promyelocytic leukemia.
Its efficacy and toxicity are
concentration-dependent and are related to
the fractions of different arsenic species and
the degree of methylation. In this study,
arsenic trioxide was given parenterally to
rabbits as a single dose or as a daily dose (0.2,
0.6 and 1.5 mg/kg) for 30 days. The blood
and organ concentrations of the arsenic
species, including As(III), DMA and MMA,
were studied on day-1 (single-dose study),
day-30 (multiple dosing study) and day-60
(reversibility study). The results showed that
As(III) was the major detectable arsenic
species in the blood. The pharmacokinetic
parameters (total clearance, area under the
curve, etc) for As(III) indicated a limit for the
capacity to eliminate As(III) at the dose of
1.5 mg/kg, and were quite the same after a
single or chronic multiple dosing. In tissues,
DMA was found to be the major metabolite
and the concentrations of DMA, As(III), and
MMA in general increased with the dose,
with the increase most significant at a dose of
1.5 mg/kg. However, normalized tissue
distribution of As(III) in the kidney on day-1,
but not on day-30, was nonlinear. Along with
decreased levels of As(III) and increased
2
levels of DMA, an inducible capacity of
methylating As(III) to DMA after chronic
dosing in kidney was suggested. The tissue
concentration of DMA was highest in lung
and liver, and the normalized tissue
distributions in liver on day-30 were
nonlinear, suggesting a limit in eliminating
DMA after a chronic high load of As(III).
Tissue concentrations of As(III), DMA and
MMA in bladder increased dramatically after
chronic dosing. However, after wash-out for
30 days, As(III), DMA and MMA were all
undetectable in bladder and liver. But,
As(III) in hair and low levels of DMA in lung,
kidney, heart and hair were still detected. In
conclusion, in rabbits we found a similar
pharmacological profile after a single or
chronic multiple dosing of parenteral arsenic
trioxide, with a limiting metabolizing
capacity at the dose of 1.5 mg/kg. Tissue
accumulation of arsenic species, mainly
DMA, and its reversibility after washout
were tissue-selective. The potential for late
toxicities of arsenic trioxide in organs with
significant tendency for arsenic accumulation
and low reversibility should be closely
monitored.
Subjects
arsenic trioxide
heart
MMA
DMA
electrophysiology
Publisher
臺北市：國立臺灣大學醫學院小兒科
Type
report
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