Metabolites Monomethylarsonic Acid Research Articles

Exposure of the general French population to metals and metalloids in 2014–2016: Results from the Esteban study

BackgroundThe purpose of the Esteban study was to describe levels of various biomarkers of exposure to several environmental pollutants, including metals and metalloids, among the French population. This paper describes the distribution of concentrations of 28 metals and metalloids in two different populations, and estimates the main determinants of exposure to total arsenic, the sum of inorganic arsenic (iAs) and its two metabolites monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), cadmium, chromium, copper, mercury and nickel. MethodsEsteban is a cross-sectional study conducted between 2014 and 2016 on a random sample of 2503 adults (18–74 years old) and 1104 children (6–17 years old) from the general population. The data collected included biological samples (blood, hair, and urines), socio-demographic characteristics, environmental and occupational exposure, and information on dietary factors and lifestyle. The geometric mean and percentiles of the distribution were estimated for each metal. Multivariate analyses were performed to identify the determinants of exposure using a generalized linear model. ResultsOnly four metals had a quantification rate below 90% in adults (beryllium, iridium, palladium, and platinum), and three metals in children (beryllium, iridium, and platinum). The concentrations of total arsenic, cadmium, chromium and mercury were higher than those found in most international studies. The determinants significantly associated with exposure were mainly diet and smoking. ConclusionsEsteban provided a nationwide description of 28 metal and metalloid exposure levels for adults (some never measured before) and for the first time in children. The study results highlighted widespread exposure to several metals and metalloids. These results could be used to advocate public health decisions for continued efforts to reduce harmful exposure to toxic metals. The Reference values (RV95) built from Esteban could also be used to support future government strategies.

Genetic Susceptibility to Neurotoxicity Related to Prenatal Inorganic Arsenic Exposure in Young Spanish Children.

We explored the influence of child and maternal single nucleotide polymorphisms (SNPs) in genes related to neurological function and arsenic metabolism (i.e., ABCA1, ABCB1, PON1, CYP3A, BDNF, GSTP1, MT2A, and APOE as well as AS3MT) on the association between prenatal arsenic (As) exposure and methylation efficiency and neuropsychological development in 4-5-year-old children. Participants were 549 mother-child pairs from the INMA (Environment and Childhood) Spanish Project. We measured inorganic arsenic (iAs) and the metabolites monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in urine samples collected during pregnancy. Neuropsychological development was assessed at the age of 4-5 years using the McCarthy Scales of Children's Abilities (MSCA). Several SNPs were determined in maternal and child DNA; AS3MT and APOE haplotypes were inferred. The median ∑As (sum of iAs, DMA, and MMA) was 7.08 μg/g creatinine. Statistically significant interactions for children's APOE haplotype were observed. Specifically, ε4-carrier children had consistently lower MSCA scores in several scales with increasing ∑As and MMA concentrations. These results provide evidence regarding the neurotoxic effects of early life exposure to As, observing that the APOE ε4 allele could make children more vulnerable to this exposure.

Influence of genetic polymorphisms on arsenic methylation efficiency during pregnancy: Evidence from a Spanish birth cohort

BackgroundInorganic arsenic (iAs) is a widespread toxic metalloid. It is well-known that iAs metabolism and its toxicity are mediated by polymorphisms in AS3MT and other genes. However, studies during pregnancy are scarce. We aimed to examine the role of genetic polymorphisms in AS3MT, GSTO2, N6AMT1, MTHFR, MTR, FTCD, CBS, and FOLH1 in iAs methylation efficiency during pregnancy. MethodsThe study included 541 pregnant participants from the INMA (Environment and Childhood) Spanish cohort. Using high-performance liquid chromatography coupled to inductively coupled plasma-tandem mass, we measured arsenic (iAs and the metabolites monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)) in urine samples collected during the first trimester. iAs methylation efficiency was determined based on relative concentrations of the As metabolites in urine (%MMA, %DMA, and %iAs). Thirty-two single nucleotide polymorphisms (SNPs) in nine genes were determined in maternal DNA; AS3MT haplotypes were inferred. We assessed the association between genotypes/haplotypes and maternal As methylation efficiency using multivariate linear regression models. ResultsThe median %MMA and %DMA were 5.3 %, and 89 %, respectively. Ancestral alleles of AS3MT SNPs (rs3740393, rs3740390, rs11191453, and rs11191454) were significantly associated with higher %MMA, %iAs, and lower %DMA. Pregnant participants with zero copies of the GGCTTCAC AS3MT haplotype presented a higher %MMA. Statistically significant associations were also found for the FOLH1 SNP rs202676 (β 0.89 95%CI: 0.24, 1.55 for carriers of the G allele vs. the A allele). ConclusionsOur study shows that ancestral alleles in AS3MT polymorphisms were associated with lower As methylation efficiency in early pregnancy and suggests that FOLH1 also plays a role in As methylation efficiency. These results support the hypothesis that As metabolism is multigenic, being a key element for identifying susceptible populations.

Inorganic arsenic induces MDM2, p53, and their phosphorylation and affects the MDM2/p53 complex in vitro.

Arsenic, as a human carcinogen, has posed a certain threat to environmental health globally. However, the underlying mechanism of the arsenic carcinogenic effect remains largely undetermined. The up-regulation of MDM2 seems to play a crucial part in tumors in especial carcinomas of the diffuse type. The interaction of MDM2 and p53 is closely relevant to the pathogenesis of tumors. In this study, we aimed to investigate the effect on MDM2, p53, and their phosphorylation after As(III). In the epidemiological study, we investigated that MDM2 expression was up-regulation and was positively linked to methylated metabolites (monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)) after As(III)-exposure. In vitro studies employing A549 and 16HBE cells confirmed the epidemiological data. Studies on MDM2 phosphorylation sites consisting of Ser166, Ser260, and Ser394 in response to arsenic exposure, which have not been studied presently, indicated that As(III) could induce the expression of MDM2 phosphorylation. Moreover, we studied the alterations of p53 and its N-terminus phosphorylation sites of Ser9, Ser15, and Ser33, which demonstrated that p53 and its phosphorylation were highly expressed after As(III) exposure. Subsequently, Co-immunoprecipitation assays validated our hypothesis that the bonding of MDM2 and p53 was altered by arsenic exposure. What's more, outcomes coming from different cell types of A549, 16HBE, and 60T-16HBE revealed that MDM2 and its phosphorylation expression existed a significant difference. The study provides evidence that As(III) and its methylated metabolites modulate the expression of MDM2, p53, and their phosphorylation and then affect the interaction between MDM2 and p53.

Prenatal arsenic exposure, arsenic methylation efficiency, and neuropsychological development among preschool children in a Spanish birth cohort

BackgroundPrenatal arsenic (As) exposure could negatively affect child neuropsychological development, but the current evidence is inconclusive. ObjectivesTo explore the relationship between prenatal urinary total As (TAs) concentrations, the As species and the methylation efficiency, and child neuropsychological development in a Spanish birth cohort. We also studied the effect modification produced by sex and several nutrients and elements. Materials and methodsStudy subjects were 807 mother–child pairs participating in the INMA (Childhood and Environment) Project. Urinary TAs and its metabolites, monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), inorganic As (iAs) and arsenobetaine were measured in the first trimester of pregnancy. Methylation efficiency was determined through the percentages of the metabolites and using principal component analysis. Children's neuropsychological development was assessed at the age of 4–5 years using the McCarthy Scales of Children's Abilities (MSCA). Multivariable linear regression models were built to assess the association between TAs, the As species and the maternal methylation efficiency, and the neuropsychological scores. We explored effect modification by sex, iron status, maternal nutrients status (serum manganese and selenium, and urinary zinc), and maternal vitamins intake (folate, and vitamins B12 and B6). ResultsThe geometric mean (95%CI) of ∑As (sum of DMA, MMA and iAs) was 7.78 (7.41, 8.17) μg/g creatinine. MMA concentrations were inversely associated with the scores for the general, verbal, quantitative, memory, executive function and working memory scales (i.e. β [CI95%] = −1.37 [-2.33, −0.41] for the general scale). An inverse association between %MMA and the memory scores was found. Children whose mothers had lower manganese, zinc and ferritin concentrations obtained lower scores on several MSCA scales with decreasing As methylation efficiency. DiscussionAn inverse association was observed between MMA concentrations and children's neuropsychological development. Maternal levels of manganese, zinc and ferritin affected the association between As methylation efficiency and MSCA scores.

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

BackgroundArsenic 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.MethodsA 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.ResultsThe 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).ConclusionsThe 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.

Association between maternal urinary speciated arsenic concentrations and gestational diabetes in a cohort of Canadian women

BackgroundEpidemiological and toxicological evidence suggests that maternal total arsenic (As) levels are associated with an elevated risk of gestational diabetes (GDM). Uncertainty remains regarding the metabolic toxicity of specific arsenic species, comprised of both organic and inorganic sources of arsenic exposure. ObjectivesWe assessed associations between speciated As and GDM using data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study. MethodsConcentrations of speciated As [(inorganic (trivalent, pentavalent)), methylated arsenic species metabolites (monomethylarsonic acid (MMA), dimethylarsinic acid (DMA)), and organic (arsenobetaine)] were measured in first trimester maternal urine samples. GDM cases were identified in accordance with Canadian guidelines. Multivariable regression models were used to estimate associations between speciated As and GDM, evaluate potential interaction between speciated As exposures, and assess fetal sex-specific findings. ResultsAmong 1243 women who had a live, singleton birth and no previous history of diabetes, 4% met the diagnostic criteria for GDM. Our analyses focused on DMA and arsenobetaine as these were the subtypes with detectable concentrations in at least 40% of samples. Compared to women in the lowest tertile of DMA (<1.49 μg As/L), women with concentrations exceeding 3.52 μg As/L (3rd tertile) experienced an increased risk of GDM (aOR = 3.86; 95% CI: 1.18, 12.57) (p-value for trend across tertiles = 0.04). When restricted to women carrying male infants, the magnitude of this association increased (aOR 3rd tertile = 4.71; 95% CI: 1.05, 21.10). ConclusionsThese results suggest a positive relation between DMA and GDM; potential differences in risk by fetal sex requires further investigation.

Arsenic Exposure in Relation to Ischemic Stroke: The Reasons for Geographic and Racial Differences in Stroke Study.

The purpose of this case-cohort study was to examine urinary arsenic levels in relation to incident ischemic stroke in the United States. We performed a case-cohort study nested within the REGARDS (REasons for Geographic and Racial Differences in Stroke) cohort. A subcohort (n=2486) of controls was randomly sampled within region-race-sex strata while all incident ischemic stroke cases from the full REGARDS cohort (n=671) were included. Baseline urinary arsenic was measured by inductively coupled plasma-mass spectrometry. Arsenic species, including urinary inorganic arsenic and its metabolites monomethylarsonic acid and dimethylarsinic acid, were measured in a random subset (n=199). Weighted Cox's proportional hazards models were used to calculate hazard ratios and 95% confidence intervals of ischemic stroke by arsenic and its species. The average follow-up was 6.7 years. Although incident ischemic stroke showed no association with total arsenic or total inorganic arsenic, for each unit higher level of urinary monomethylarsonic acid on a log-scale, after adjustment for potential confounders, ischemic stroke risk increased ≈2-fold (hazard ratio=1.98; 95% confidence interval: 1.12-3.50). Effect modification by age, race, sex, or geographic region was not evident. A metabolite of arsenic was positively associated with incident ischemic stroke in this case-cohort study of the US general population, a low-to-moderate exposure area. Overall, these findings suggest a potential role for arsenic methylation in the pathogenesis of stroke, having important implications for future cerebrovascular research.

Urinary arsenic levels in the French adult population: The French National Nutrition and Health Study, 2006–2007

The French Nutrition and Health Survey (ENNS) was conducted to describe dietary intakes, nutritional status, physical activity, and levels of various biomarkers for environmental chemicals (heavy metals and pesticides) in the French population (adults aged 18–74years and children aged 3–17years living in continental France in 2006–2007). The aim of this paper was to describe the distributions of total arsenic and the sum of iAs+MMA+DMA in the general adult population, and to present their main risk factors.In the arsenic study, 1500 and 1515 adults (requested to avoid seafood intake in the previous 3days preceding urine collection) were included respectively for the analysis of the sum of inorganic arsenic (iAs) and its two metabolites, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), and for the total arsenic. Results were presented as geometric means and selected percentiles of urinary arsenic concentrations (μg/L) and creatinine-adjusted urinary arsenic (μg/g of creatinine) for total arsenic, and the sum of inorganic arsenic and metabolites (iAs+MMA+DMA). The geometric mean concentration of the sum of iAs+MMA+DMA in the adult population living in France was 3.34μg/g of creatinine [3.23–3.45] (3.75μg/L [3.61–3.90]) with a 95th percentile of 8.9μg/g of creatinine (10.68μg/L). The geometric mean concentration of total arsenic was 11.96μg/g of creatinine [11.41–12.53] (13.42μg/L [12.77–14.09]) with a 95th percentile of 61.29μg/g of creatinine (72.75μg/L).Urinary concentrations of total arsenic and iAS+MMA+DMA were influenced by sociodemographic and economic factors, and by risk factors such as consumption of seafood products and of wine. In our study, covariate-adjusted geometric means demonstrated several slight differences, due to consumption of fish, shellfish/crustaceans or wine.This study provides the first reference value for arsenic in a representative sample of the French population not particularly exposed to high levels of arsenic (10μg/g of creatinine). It shows that urinary arsenic concentrations in the French adult population (in particular concentrations of iAs+MMA+DMA) were relatively low compared with foreign data.

Genetic polymorphisms in glutathione S-transferase (GST) superfamily and risk of arsenic-induced urothelial carcinoma in residents of southwestern Taiwan

BackgroundArsenic exposure is an important public health issue worldwide. Dose-response relationship between arsenic exposure and risk of urothelial carcinoma (UC) is consistently observed. Inorganic arsenic is methylated to form the metabolites monomethylarsonic acid and dimethylarsinic acid while ingested. Variations in capacity of xenobiotic detoxification and arsenic methylation might explain individual variation in susceptibility to arsenic-induced cancers.MethodsTo estimate individual susceptibility to arsenic-induced UC, 764 DNA specimens from our long-term follow-up cohort in Southwestern Taiwan were used and the genetic polymorphisms in GSTM1, GSTT1, GSTP1 and arsenic methylation enzymes including GSTO1 and GSTO2 were genotyped.ResultsThe GSTT1 null was marginally associated with increased urothelial carcinoma (UC) risk (HR, 1.91, 95% CI, 1.00-3.65), while the association was not observed for other GSTs. Among the subjects with cumulative arsenic exposure (CAE) ≥ 20 mg/L*year, the GSTT1 null genotype conferred a significantly increased cancer risk (RR, 3.25, 95% CI, 1.20-8.80). The gene-environment interaction between the GSTT1 and high arsenic exposure with respect to cancer risk was statistically significant (multiplicative model, p = 0.0151) and etiologic fraction was as high as 0.86 (95% CI, 0.51-1.22). The genetic effects of GSTO1/GSTO2 were largely confined to high arsenic level (CAE ≥ 20). Diplotype analysis showed that among subjects exposed to high levels of arsenic, the AGG/AGG variant of GSTO1 Ala140Asp, GSTO2 5'UTR (-183)A/G, and GSTO2 Asn142Asp was associated with an increased cancer risk (HRs, 4.91, 95% CI, 1.02-23.74) when compared to the all-wildtype reference, respectively.ConclusionsThe GSTs do not play a critical role in arsenic-induced urothelial carcinogenesis. The genetic effects of GSTT1 and GSTO1 on arsenic-induced urothelial carcinogenesis are largely confined to very high exposure level.

Association between arsenic exposure and behavior among first-graders from Torreón, Mexico

Previous studies suggest adverse effects of arsenic exposure on children’s cognitive function. In this study, we examined the potential association between arsenic exposure and children’s behavior. Five hundred and twenty-six children, 6–7 years old, living near a metal foundry in Torreón, Mexico, participated in the study. Arsenic exposure was measured as total urinary arsenic (UAs) and arsenic metabolites—monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) concentrations. Children’s behavior was assessed by Conners Behavior Rating Scales for parents and teachers. The median (interquartile range) concentrations of UAs, MMA and DMA were 55.2 (39.7), 6.7 (5.9) and 39.3 (28.5) μg/L, respectively. The mean behavior scores from parent and teacher ratings were within the clinically normal range ( T<65). The relationship between behavior and urinary arsenic was modeled in linear and logistic regression models, with UAs, MMA and DMA tested in separate models and entered as quartiles. No significant association was found between any measure of urinary arsenic and parent ratings of behavior. However, higher UAs was modestly associated with higher scores on the Oppositional, Cognitive Problems and ADHD sub-scales of the teacher ratings; a dose–response relationship was not established between UAs quartiles and behavior. Higher urinary DMA was associated with higher ratings on the Oppositional, Cognitive Problems and ADHD Index by teachers. The associations between UAs and behavior became statistically non-significant after adjustment for the Peabody Picture Vocabulary Test scores, suggesting that the harmful effects of arsenic on behavior may be secondary to arsenic-induced cognitive deficits. These data suggest a potential adverse association between arsenic and children’s behavior and indicate a need to further study the effects of arsenic and arsenic metabolites on neurobehavioral outcomes in children.

Effects of monomethylarsonic and monomethylarsonous acid on evoked synaptic potentials in hippocampal slices of adult and young rats

Arsenite and its metabolites, dimethylarsinic or dimethylarsinous acid, have previously been shown to disturb synaptic transmission in hippocampal slices of rats (Krüger, K., Gruner, J., Madeja, M., Hartmann, L.M., Hirner, A.V., Binding, N., Muβhoff, U., 2006a. Blockade and enhancement of glutamate receptor responses in Xenopus oocytes by methylated arsenicals. Arch. Toxicol. 80, 492–501, Krüger, K., Straub, H., Binding, N., Muβhoff, U., 2006b. Effects of arsenite on long-term potentiation in hippocampal slices from adult and young rats. Toxicol. Lett. 165, 167–173, Krüger, K., Repges, H., Hippler, J., Hartmann, L.M., Hirner, A.V., Straub, H., Binding, N., Muβhoff, U., 2007. Effects of dimethylarsinic and dimethylarsinous acid on evoked synaptic potentials in hippocampal slices of young and adult rats. Toxicol. Appl. Pharmacol. 225, 40–46). The present experiments investigate, whether the important arsenic metabolites monomethylarsonic acid (MMA V) and monomethylarsonous acid (MMA III) also influence the synaptic functions of the hippocampus. In hippocampal slices of young (14–21 days-old) and adult (2–4 months-old) rats, evoked synaptic field potentials from the Schaffer collateral-CA1 synapse were measured under control conditions and during and after 30 and 60 min of application of the arsenic compounds. MMA V had no effect on the synapse functions neither in slices of adult nor in those from young rats. However, MMA III strongly influenced the synaptic transmission: it totally depressed the amplitudes of fEPSPs at concentrations of 50 μmol/l (adult rats) and 25 μmol/l (young rats) and LTP amplitudes at concentrations of 25 μmol/l (adult rats) and 10 μmol/l (young rats), respectively. In contrast, application of 1 μmol/l MMA III led to an enhancement of the LTP amplitude in young rats, which is interpretable by an enhancing effect on NMDA receptors and a lack of the blocking effect on AMPA receptors at this concentration (Krüger, K., Gruner, J., Madeja, M., Hartmann, L.M., Hirner, A.V., Binding, N., Muβhoff, U., 2006a. Blockade and enhancement of glutamate receptor responses in Xenopus oocytes by methylated arsenicals. Arch. Toxicol. 80, 492–501). These effects are probably not mediated by changes in cell excitability or in presynaptic glutamate release rates, since antidromically induced population spikes and paired-pulse facilitation failed to show any MMA III effect. The impairment of the excitatory CA1 synapse is more likely caused by the action of MMA III on postsynaptic glutamatergic receptors and may be jointly responsible for dysfunctions of cognitive effects in arsenic toxicity.

Monomethylarsonate (MMA v) exerts stronger effects than arsenate on the structure and thermotropic properties of phospholipids bilayers

Methylation of inorganic arsenic has been regarded as a detoxification mechanism because its metabolites monomethylarsonic acid (MMA v) and dimethylarsinic acid (DMA v) are supposed to be less toxic than inorganic arsenite and arsenate. In recent years, however, this interpretation has been questioned. Additionally, there are insufficient reports concerning the effects of arsenic compounds on cell membrane structure and functions. With the aim to better understand the molecular mechanisms of the interaction of MMA v and arsenate with cell membranes, we have utilized molecular models consisting in bilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), representative of phospholipid classes located in the outer and inner monolayers of many cell membranes including that of the human erythrocyte. The capacity of MMA v and arsenate to perturb the bilayer structures of DMPC and DMPE was evaluated by X-ray diffraction; the modifications of their thermotropic behavior were followed by differential scanning calorimetry (DSC), while DMPC large unilamellar vesicles (LUV) were studied by fluorescence spectroscopy. It was found that MMA v and arsenate did not structurally perturb DMPC bilayers; however, DMPE bilayers did suffer structural perturbations by MMA v. DSC measurements also revealed that DMPE's thermotropic properties were significantly affected by arsenicals, where MMA v was more effective than arsenate, whilst only slight modifications were observed in the case of DMPC-MMA v system.

Pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory acute promyelocytic leukemia treated with arsenic trioxide

To investigate the pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory acute promyelocytic leukemia (APL) treated with arsenic trioxide (ATO) at a daily dose of 0.15 mg/kg. Inorganic arsenic (AsIII and AsV) and the major metabolites monomethylarsonic acid (MAA(V)) and dimethylarsinic acid (DMAA(V)) in plasma and urine collected from 12 Japanese patients were quantified by HPLC/ICP-MS. The plasma concentrations of AsIII and AsV on day 1 reached the similar Cmax (12.4 +/- 8.4 and 10.2 +/- 3.9 ng/ml) immediately after completion of administration followed by a biphasic elimination. The AUC(0-infinity) of AsV was about twice that of AsIII. The appearance of methylated metabolites in the blood was delayed. During the repeated administration, the plasma concentrations of inorganic arsenic reached the steady state. In contrast, the MAA(V) and DMAA(V) concentrations increased in relation to increased administration frequency. The mean total arsenic excretion rate including inorganic arsenic and methylated arsenic was about 20% of daily dose on day 1 and remained at about 60% of daily dose during week 1-4. This study demonstrates that ATO is metabolized when administered intravenously to APL patients and methylated metabolites are promptly eliminated from the blood and excreted into urine after completion of administration, indicating no measurable accumulation of ATO in the blood.

Pharmacokinetics of Arsenic Species with Relapsed or Refractory Acute Promyelocytic Leukemia (APL) Treated with Arsenic Trioxide (ATO) in Japanese Patients.

Background: The therapy with ATO induced high complete remission and maintained for long survival for patients with relapsed or refractory APL. While the clinical effect of ATO against APL was confirmed, its pharmacokinetics has yet to be clarified. In most reports on pharmacokinetics of ATO, the arsenic concentrations were measured as total arsenic. We investigated the pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory APL treated with ATO.Patients and Methods: In the prospective study, from 12 patients with APL treated with ATO, the blood and urine for the pharmacokinetic data were collected and subsequently stored frozen until analysis. ATO (0.15 mg/kg) was intravenously administered once daily over 2 hours to until bone marrow remission to a maximum of 60 days. The plasma and urine were collected on day 1 and after 1, 2 and 4 weeks. Inorganic arsenic (AsIII and AsV) and the major metabolites monomethylarsonic acid (MAAV) and dimethylarsinic acid (DMAAV) in plasma and urine were quantified by HPLC/ICP-MS.Results: Ten of 12 patients (83%) achieved complete remission (CR). Six of ten (60%) who achieved CR were negative in the post-treatment RT-PCR test. For two patients the blood and urine were collected also during consolidation. The plasma concentrations of inorganic arsenic on day 1 reached the Cmax (mean 22.6±11.4 ng/mL) immediately after completion of administration followed by a biphasic elimination while the appearance of methylated metabolites in the blood was delayed. During the repeated administration, the plasma concentrations of inorganic arsenic reached the steady-state. The Cmax of inorganic arsenic on week 4 was similar (mean 23.2±10.2 ng/mL) but the elimination was delayed. As a result, the AUC increased about 2-fold (from mean 211.8±55.1 to 474.8±192.6 ng/mL), and the clearance declined (from 0.7±0.2 to 0.4±0.1 L/kg/h) but no marked change was observed in volume of distribution. In contrast, the MAAV and DMAAV concentrations increased in relation to increased administration frequency fold (from mean 3.1±1.6, 5.4±2.9 to 10.9±4.7, 21.4±12.3 ng/mL). The plasma concentrations of arsenobetaine, an organic arsenic compound derived from seafood, remained almost constant (about 2 mg/mL) during the study period. The urinary excretion rates of AsIII and AsV remained almost constant after week 1, suggesting that the steady-state was attained. In contrast, a tendency to increase with administration frequency was observed in the excretion rates of MAAV and DMAAV after week 4 (from mean 17.4±11.2, 19.4±8.5 to 19.6±10.0, 21.1±9.5 %). The total arsenic excretion rate remained at ~60% of dose after week 1.Conclusion: ATO is metabolized when administered intravenously to APL patients and methylated metabolites were promptly eliminated from the blood and excreted into urine after completion of administration, indicating no measurable accumulation of ATO in the blood.

Pharmacokinetics (PK) of arsenic trioxide in cancer patients (pts) with renal dysfunction: Preliminary results

2018 Background: Trisenox (arsenic trioxide- ATO) is approved for treatment of relapsed/refractory acute promyelocytic leukemia. This study was designed to determine the PK of ATO in adult cancer pts with renal dysfunction and to evaluate its safety. Methods: 14 pts (median age 66 yrs, 29–85) in 4 renal function (RF) groups (normal- CLCR >80 mL/min; mild dysfunction: 50–80; moderate: 30–49; severe: <30) received IV ATO 0.15 mg/kg/d twice weekly for 4 wks, followed by 2 weeks without drug. Pts were treated for 2 six-week cycles. Arsenious acid (AsIII), arsenic acid (AsV), monomethyl arsonic acid (MMA), and dimethylarsinic acid (DMA) concentrations in plasma and urine were determined by validated methods based on anion exchange HPLC combined with ICPMS. Results: AsIII was rapidly distributed throughout the body (Table). MMA and DMA concentrations reached maximum values 24 hr after ATO. Urinary excretion of all As-containing species accounted for 27% of the dose (days 1–3). No significant correlations were found between AsIII PK parameters and RF, expressed by the CLCR value, except for urinary excretion, which was linearly correlated with CLCR (p<0.01). Exposure to inactive metabolites MMA and DMA inversely correlated with RF (p<0.05). After repeated dosing, plasma concentrations and excretion of methylated metabolites in urine were greater than those observed after the 1st administration, suggesting accumulation. The only severe drug-related toxicity was 1 grade 3 hyperglycemia. Conclusions: Renal excretion does not appear to be the main elimination route for AsIII, which is extensively metabolized to MMA and DMA. Systemic exposure of patients to AsIII, the active species, appears unaffected by RF, even in pts with severe dysfunction. Some accumulation of slowly eliminated metabolites MMA and DMA occurs on repeated dosing. ATO is well-tolerated at this dose in this pt population. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cell Therapeutics, Inc. Cell Therapeutics, Inc. Cell Therapeutics, Inc. Cell Therapeutics, Inc.

Pharmacokinetics (PK) of arsenic trioxide in cancer patients (pts) with renal dysfunction: Preliminary results

2018 Background: Trisenox (arsenic trioxide- ATO) is approved for treatment of relapsed/refractory acute promyelocytic leukemia. This study was designed to determine the PK of ATO in adult cancer pts with renal dysfunction and to evaluate its safety. Methods: 14 pts (median age 66 yrs, 29–85) in 4 renal function (RF) groups (normal- CLCR >80 mL/min; mild dysfunction: 50–80; moderate: 30–49; severe: <30) received IV ATO 0.15 mg/kg/d twice weekly for 4 wks, followed by 2 weeks without drug. Pts were treated for 2 six-week cycles. Arsenious acid (AsIII), arsenic acid (AsV), monomethyl arsonic acid (MMA), and dimethylarsinic acid (DMA) concentrations in plasma and urine were determined by validated methods based on anion exchange HPLC combined with ICPMS. Results: AsIII was rapidly distributed throughout the body (Table). MMA and DMA concentrations reached maximum values 24 hr after ATO. Urinary excretion of all As-containing species accounted for 27% of the dose (days 1–3). No significant correlations were found between AsIII PK parameters and RF, expressed by the CLCR value, except for urinary excretion, which was linearly correlated with CLCR (p<0.01). Exposure to inactive metabolites MMA and DMA inversely correlated with RF (p<0.05). After repeated dosing, plasma concentrations and excretion of methylated metabolites in urine were greater than those observed after the 1st administration, suggesting accumulation. The only severe drug-related toxicity was 1 grade 3 hyperglycemia. Conclusions: Renal excretion does not appear to be the main elimination route for AsIII, which is extensively metabolized to MMA and DMA. Systemic exposure of patients to AsIII, the active species, appears unaffected by RF, even in pts with severe dysfunction. Some accumulation of slowly eliminated metabolites MMA and DMA occurs on repeated dosing. ATO is well-tolerated at this dose in this pt population. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cell Therapeutics, Inc. Cell Therapeutics, Inc. Cell Therapeutics, Inc. Cell Therapeutics, Inc.

Arsenic Speciation in Human Organs following Fatal Arsenic Trioxide Poisoning—A Case Report

The aim of this investigation was to study the distribution of arsenic species in human organs following fatal acute intoxication by arsenic trioxide. The collected autopsy samples of most organs were ground and dried, and the total arsenic was measured by electrothermal atomic absorption spectrometry (ETAAS). The arsenic species--inorganic arsenic, in the form of arsenite [As(III)] and arsenate [As(V)], and its metabolites [monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)]--were quantified by ETAAS after extraction with methanol/water (1:1, by volume) and separation by HPLC. The results indicate that after acute intoxication, the liver and kidneys show the highest concentrations of total arsenic and that the total concentration in blood is 7- to 350-fold less concentrated than in organs. In all organs, As(III) is the predominant species, and MMA is more concentrated than DMA. MMA and DMA are more prevalent in lipidic organs (49% of total arsenic) compared with other organs (25% of total arsenic). As(V) was found in small quantities in the liver, kidneys, and blood.