scholarly journals Pharmacokinetic Characteristics, Tissue Bioaccumulation and Toxicity Profiles of Oral Arsenic Trioxide in Rats: Implications for the Treatment and Risk Assessment of Acute Promyelocytic Leukemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Wensheng Liu ◽  
Bin Wang ◽  
Yilei Zhao ◽  
Zhiqiang Wu ◽  
Andi Dong ◽  
...  
Keyword(s):  
Oral Administration ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Whole Blood ◽  
Promyelocytic Leukemia ◽  
Absolute Bioavailability ◽  
Control Group ◽  
Atomic Fluorescence Spectrometry ◽  
Maximum Plasma ◽  
Arsenic Metabolites

Oral arsenic trioxide (ATO) has demonstrated a favorable clinical efficiency in the treatment of acute promyelocytic leukemia (APL). However, the pharmacokinetic characteristics, tissue bioaccumulation, and toxicity profiles of arsenic metabolites in vivo following oral administration of ATO have not yet been characterized. The present study uses high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) to assess the pharmacokinetics of arsenic metabolites in rat plasma after oral and intravenous administration of 1 mg kg−1 ATO. In addition, the bioaccumulation of arsenic metabolites in blood and selected tissues were evaluated after 28 days oral administration of ATO in rats at a dose of 0, 2, 8, and 20 mg kg−1 d−1. The HPLC-HG-AFS analysis was complemented by a biochemical, hematological, and histopathological evaluation conducted upon completion of ATO treatment. Pharmacokinetic results showed that arsenite (AsIII) reached a maximum plasma concentration rapidly after initial dosing, and the absolute bioavailability of AsIII was 81.03%. Toxicological results showed that the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and white blood cells (WBC) in the 20 mg kg−1 d−1 ATO group were significantly increased compared to the control group (p < 0.05). The distribution trend of total arsenic in the rat was as follows: whole blood > kidney > liver > heart. Dimethylated arsenic (DMA) was the predominant bioaccumulative metabolite in the whole blood, liver, and heart, while monomethylated arsenic (MMA) was the predominant one in the kidney. Collectively, these results revealed that oral ATO was rapidly absorbed, well-tolerated, and showed organ-specific and dose-specific bioaccumulation of arsenic metabolites. The present study provides preliminary evidence for clinical applications and the long-term safety evaluation of oral ATO in the treatment of APL.

The Clinical Observation on Arsenic Trioxide with ATRA in Treating Acute Promyelocytic Leukemia for Six Years.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2868-2868 ◽  
Author(s):  
Zhou Zhong ◽  
Zhen-cai Liu ◽  
Jian-wei Li
Keyword(s):  
Side Effects ◽  
Complete Remission ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Relapse Rate ◽  
Severe Infection ◽  
Myocardial Damage ◽  
Promyelocytic Leukemia ◽  
Control Group ◽  
Treatment Side Effects

Abstract Objective: To observe the efficacy of arsenic trioxide(AS2O3) with ATRT for the treatment of patients with acute promyelocytic leukemia(APL). Methods: Seventy-four patients with APL, from 2000 to 2006, were randomly divided into two groups. Thirty-eight patients as treating group received AS2O3+ATRA, another thirty-six patients as control group were treated only AS2O3+ARTA+chemotherapy(DA or HA). Results: The first induced complete remission (CR) was 100%, the three-year relapse rate was 2.6%, the six-year continuous complete remission(CCR) rate was 94.6% for treating group. The rate of CR, the three-year relapse and CCR were 81.3%, 30.7% and 61.5% respectively for control group. The side effects such as myelosuppression, severe infection or septicemia, hepatic, renal and myocardial damage, and the digestive tract side effect were mild compared with that in control group(p<0.01). In treating group, the hyperleukocytosis was not observed, Incidence of the three-year treatment-related mortality (TRM) was 0%, the control group was 16.7%. Conclusion: The combination of AS2O3 and ATRA can obtain a higher CCR, low relapse rate and mild treatment side effects.

Determination of arsenic metabolites in patients with newly diagnosed acute promyelocytic leukemia treated with arsenic trioxide

2013 ◽  
Vol 54 (9) ◽  
pp. 2041-2046 ◽  
Author(s):  
Zhuo Zhang ◽  
Yan Chen ◽  
Hongbin Meng ◽  
Meijuan Sui ◽  
Qian Zhou ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Newly Diagnosed ◽  
Arsenic Metabolites

scholarly journals Importance of monitoring arsenic methylation metabolism in acute promyelocytic leukemia patients receiving the treatment of arsenic trioxide

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Yu Zheng ◽  
Yuan-Fei Mao ◽  
Hui-Jin Zhao ◽  
Li Chen ◽  
Li-Ning Wang ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Arsenic Speciation ◽  
Promyelocytic Leukemia ◽  
Chronic Liver ◽  
Dimethylarsinic Acid ◽  
Metabolic Pattern ◽  
Methylation Index ◽  
Arsenic Methylation

Abstract Background Arsenic trioxide [ATO, inorganic arsenite (iAsIII) in solution] plays an important role in the treatment of acute promyelocytic leukemia (APL). However, the long-term adverse effects (AEs) and the retention of arsenic among APL patients are rarely reported. In this study, we focused on arsenic methylation metabolism and its relationship with chronic hepatic toxicity, as we previously reported, among APL patients who had finished the treatment of ATO. Methods A total of 112 de novo APL patients who had completed the ATO-containing treatment were enrolled in the study. Arsenic species [iAsIII, inorganic arsenate (iAsV), and their organic metabolites, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)] in patients’ plasma, urine, hair and nails were detected by high-performance liquid chromatography combined with inductively coupled plasma mass spectrometry (HPLC-ICP-MS). Eighteen single nucleotide polymorphisms (SNPs) of the arsenic (+ 3 oxidative state) methylation transferase (AS3MT) gene, which was known as the main catalyzer for arsenic methylation, were tested with the polymerase chain reaction method. Results The study showed the metabolic pattern of arsenic in APL patients undergoing and after the treatment of ATO, in terms of total arsenic (TAs) and four species of arsenic. TAs decreased to normal after 6 months since cessation of ATO. But the arsenic speciation demonstrated significantly higher portion of iAsIII in patient’s urine (40.08% vs. 1.94%, P < 0.001), hair (29.25% vs. 13.29%, P = 0.002) and nails (30.21% vs. 13.64%, P = 0.003) than the healthy controls’, indicating a decreased capacity of arsenic methylation metabolism after the treatment of ATO. Urine primary methylation index (PMI) was significantly lower in patients with both chronic liver dysfunction (0.14 vs. 0.28, P = 0.047) and hepatic steatosis (0.19 vs. 0.3, P = 0.027), suggesting that insufficient methylation of arsenic might be related to chronic liver disorders. Two SNPs (A9749G and A27215G) of the AS3MT gene were associated with impaired urine secondary methylation index (SMI). Conclusions The long-term follow-up of arsenic speciation indicated a decreased arsenic methylation metabolism and a probable relationship with chronic hepatic disorders among APL patients after the cessation of ATO. Urine PMI could be a monitoring index for chronic AEs of ATO, and the SNPs of AS3MT gene should be considered when determining the dosage of ATO.

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