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

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.

Arsenic-Related Health Risk Assessment of Realgar-Containing NiuHuangJieDu Tablets in Healthy Volunteers Po Administration

“…To date, several analytical methods have been used for arsenic determination in biological samples, such as hydride generationatomic fluorescence spectrometry (HG-AFS) and inductivelycoupled plasma-mass spectrometry (ICP-MS) (Wegwerth et al, 2021;Liu et al, 2021). HG-AFS is a suitable alternative to ICP-MS in the detection limit, which has the advantages of lower cost, shorter preheating time, and easier operation.…”

Arsenic Trioxide Therapy During Pregnancy: ATO and Its Metabolites in Maternal Blood and Amniotic Fluid of Acute Promyelocytic Leukemia Patients

“…The prototype drug As III and its metabolites are widely distributed throughout the body. The arsenic species can be detected in urine ( 11 ), plasma ( 16 ), red blood cells ( 17 ), leukocytes ( 37 ), granulocytes ( 37 ), and cerebrospinal fluid (CSF) ( 38 ) of APL patients treated with ATO, and in kidney ( 39 ), liver ( 39 ), and heart ( 39 ) of rat treated with ATO. In this study, the C trough , percentage, and methylation index of arsenic species in plasma from pregnant and non-pregnant women treated with ATO were evaluated.…”

Update of the risk assessment of inorganic arsenic in food

“…In cells in culture, it induces more severe genotoxic effects, apoptosis and oxidative stress than sodium arsenite (Jiang et al., 2013 ). Differences in toxicokinetics between the two arsenical compounds might account for the stronger toxic effects induced by arsenic trioxide (Liu et al., 2021 ). Three studies of genotoxicity in rodents upon oral administration of arsenic trioxide have been identified and they are reported below.…”