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. 2021 May 28:12:647687.
doi: 10.3389/fphar.2021.647687. eCollection 2021.

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

Wensheng Liu  1 , Bin Wang  1 , Yilei Zhao  1 , Zhiqiang Wu  1 , Andi Dong  1 , Hongzhu Chen  1 , Liwang Lin  1 , Jing Lu  1 , Xin Hai  1
Affiliations

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

Wensheng Liu et al. Front Pharmacol. .

Abstract

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.

Keywords: acute promyelocytic leukemia; arsenic toxicity; dimethylated arsenic; monomethylated arsenic; oral arsenic trioxide; pharmacokinetics; tissue bioaccumulation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Pharmacokinetics and toxicology study in rats administered with oral ATO.
FIGURE 2
FIGURE 2
Mean plasma concentration-time curves of rats AsIII, AsV, MMAV, and DMAV after intragastric (A–D) and intravenous (E–H) administration to a single dose (1 mg kg−1). Data were shown as mean ± SEM. (n = 5 for each group).
FIGURE 3
FIGURE 3
Mean body weight of male rats (A) and female rats (B) following intragastric administration of ATO for 28 days, respectively (mean ± SEM, n = 6 for each group). ** indicates statistically different from the control group (0 mg kg−1 d−1) at the 0.01 level.
FIGURE 4
FIGURE 4
Representative histopathology slices of rats liver (A), kidney (B), heart (C) following the intragastric administration of ATO for 28 days (i) 0 mg kg−1 d−1, control group; (ii) 2 mg kg−1 d−1 group; (iii) 8 mg kg−1 d−1 group; (iv) 20 mg kg−1 d−1 group (H&E Stain, magnification ×400).
FIGURE 5
FIGURE 5
Total arsenic concentration in rat tissues following 28 days intragastric administration of different doses of ATO. Total arsenic concentration in the blood (A), liver (B), kidney (C), heart (D). Asterisks indicate statistical differences compared to the control group (0 mg kg−1 d−1) at p < 0.05 (*); p < 0.01 (**); p < 0.001 (***). ###: statistical difference compared to the 8 mg kg−1 d−1 group (p < 0.001).
FIGURE 6
FIGURE 6
The distribution of total arsenic in whole blood and tissue samples after intragastric administration of ATO for 28 days.
See this image and copyright information in PMC

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