Monomethylated arsenic was the Major methylated arsenic in Red blood cells of acute promyelocytic leukemia patients treated with arsenic trioxide.

BACKGROUND: Arsenic trioxide (ATO) has been successfully applied in the treatment of acute promyelocytic leukemia (APL). Arsenic metabolites including inorganic arsenic and methylated arsenic could lead to different toxicity and curative effect. This study aims to establish a method to determine arsenic species in red blood cells (RBCs), clarify the distribution characteristics of arsenic species in RBCs. METHODS: Steady state blood samples were collected from 97 APL patients. H2O2 and HClO4 were used to release the hemoglobin bounding arsenic and precipitate protein. Arsenite (iAsIII), arsenate (iAsV), monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) in plasma and RBCs were detected by HPLC-HG-AFS. Free and bound arsenic species in RBCs were separated by 30 kDa molecular mass cutoff filters and determined to evaluate hemoglobin binding capacity of different arsenic species. RESULTS: The method was validated with accuracy ranged from 84.75% to 104.13%. Arsenic species in RBCs followed the trend iAs > MMA > DMA (p < 0.01), while the concentration of DMA was significantly higher than iAs and MMA in plasma (p < 0.01). The correlation between iAs concentration in plasma and corresponding RBCs arsenic level was weak. And the concentrations of DMA and MMA in plasma were moderately positive correlated with those in RBCs. Hemoglobin-binding ratios of iAs, MMA and DMA were all over 70 %. CONCLUSIONS: In this study, we provided a reliable method to determine arsenic species in RBCs of APL patients treated with ATO by HPLC-HG-AFS. It was confirmed that the concentration of DMA is the highest in plasma, while MMA is the most predominant methylated arsenic in RBCs. High affinity of MMA with human Hb was responsible for the accumulation of arsenic in RBCs of APL patients.

Clinical pharmacokinetics and safety profile of single agent arsenic trioxide by continuous slow-rate infusion in patients with newly diagnosed acute promyelocytic leukemia.

PURPOSE: This study evaluated pharmacokinetics (PK) and safety profiles of single agent arsenic trioxide (ATO, As2O3) administrated as continuous slow-rate infusion in patients with newly diagnosed acute promyelocytic leukemia. PATIENTS AND METHODS: Patients received 0.16 mg/kg ATO per day. ATO was given for 40 min infusion on the first day followed by 18-20 h daily at a very slow rate with infusion speed of 8 drips/min. During the first week, plasma samples were collected immediately before next administration on each day, and 0.5, 1, 2, 4, 8, 12 h after administration, at the end of infusion (18 h) on day 7. Total arsenic was determined by ICPMS. Arsenic species, arsenious acid (AsIII) and its metabolites, monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV), were quantified by UHPLC-ICPMS. Safety assessment and PK analysis was conducted. RESULTS: Hyperleukocytosis occurred in two patients and no severe toxicity was observed. Total arsenic gradually accumulated from 15.84 to 34.12 ng/mL during the first week of therapy. MMAV/iAs increased and remained stable at value about 0.6 after day 4, while DMAV/MMAV declined under 2 after day 4. Compared with 2 h infusion, clearance (CL) of AsIII was significantly lower (0.8 ± 0.2 vs. 2.7 ± 1.7 L/kg/h, P = 0.002) while AUC0-t of AsIII was significantly increased (213.9 ± 38.6 vs. 82.6 ± 55.7 L/kg/h, P = 0.028). CONCLUSION: Continuous slow-rate ATO infusion provided an alternative administration for ATO therapy with few toxic effects. Degree of methylation from MMA to DMA is inconsistent with that from iAs to MMA. PK of arsenic species is considered important for clinical use of ATO.