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Kevin A. Francesconi - One of the best experts on this subject based on the ideXlab platform.
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Dose and Diet - Sources of Arsenic Intake in Mouse in Utero Exposure Scenarios.
Chemical Research in Toxicology, 2018Co-Authors: Manuela Murko, David J Thomas, Brittany Elek, Miroslav Styblo, Kevin A. FrancesconiAbstract:In humans, early life exposure to inorganic Arsenic is associated with adverse health effects. Inorganic Arsenic in utero or in early postnatal life also produces adverse health effects in offspring of pregnant mice that consumed drinking water containing low part per billion levels of inorganic Arsenic. Because aggregate exposure of pregnant mice to inorganic Arsenic from both drinking water and food has not been fully evaluated in experimental studies, quantifying Arsenic exposure of the developing mouse is problematic. Here, we determined levels of total Arsenic and Arsenic species in natural ingredient rodent diets that are composed of many plant and animal-derived foodstuffs and in a purified ingredient rodent diet that is composed of a more restricted mixture of foodstuffs. In natural ingredient diets, total Arsenic levels ranged from ∼60 to ∼400 parts per billion, and in the purified ingredient diet, total Arsenic level was 13 parts per billion. Inorganic Arsenic was the predominant Arsenic species...
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determination of the trypanocidal drug melarsoprol and its conversion products in biological fluids with hplc icpms esms
Talanta, 2013Co-Authors: Georg Raber, Thomas Raber, Reingard Raml, Manuela Murko, Christoph Magnes, Kevin A. FrancesconiAbstract:Abstract Although melarsoprol, an organoArsenic compound, is widely used for the treatment of trypanosomiasis (human African sleeping sickness), very little is known about its fate in the human body, its active metabolites passing the blood–brain barrier and the mode of action. Previous pharmacological studies based on the determination of melarsoprol by HPLC–UV or by a bioassay method produced different results. We report a HPLC–ICPMS method suitable for determining melarsoprol and its metabolites in biological fluids. The Arsenic selective capability of the method allowed the quantitative measurement of melarsoprol and two Arsenic-containing conversion products produced when melarsoprol was incubated with human serum and blood. The major product was identified as melarsen [4-[(4,6-diamino-1,3,5-triazin-2-yl)amino]phenyl]arsonic acid by HPLC/electrospray MS, and by accurate mass measurements. Investigations about the stability of melarsoprol in serum showed that within 30 h about 10% of melarsoprol is converted to melarsen. In blood, however, most of the melarsoprol was bound to proteins and only 1% was converted to melarsen after 30 hours. The limit of detection for melarsoprol and its conversion products were in the range of 1 µg As L −1 (13 nmol As L −1 ) based on signal to noise ratio of 3 with a 10 µL injection volume allowing direct determination of the compounds in blood and serum (after protein precipitation) at therapeutically realistic concentrations.
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Determination of the trypanocidal drug melarsoprol and its conversion products in biological fluids with HPLC-ICPMS/ESMS.
Talanta, 2013Co-Authors: Georg Raber, Thomas Raber, Reingard Raml, Manuela Murko, Christoph Magnes, Kevin A. FrancesconiAbstract:Abstract Although melarsoprol, an organoArsenic compound, is widely used for the treatment of trypanosomiasis (human African sleeping sickness), very little is known about its fate in the human body, its active metabolites passing the blood–brain barrier and the mode of action. Previous pharmacological studies based on the determination of melarsoprol by HPLC–UV or by a bioassay method produced different results. We report a HPLC–ICPMS method suitable for determining melarsoprol and its metabolites in biological fluids. The Arsenic selective capability of the method allowed the quantitative measurement of melarsoprol and two Arsenic-containing conversion products produced when melarsoprol was incubated with human serum and blood. The major product was identified as melarsen [4-[(4,6-diamino-1,3,5-triazin-2-yl)amino]phenyl]arsonic acid by HPLC/electrospray MS, and by accurate mass measurements. Investigations about the stability of melarsoprol in serum showed that within 30 h about 10% of melarsoprol is converted to melarsen. In blood, however, most of the melarsoprol was bound to proteins and only 1% was converted to melarsen after 30 hours. The limit of detection for melarsoprol and its conversion products were in the range of 1 µg As L −1 (13 nmol As L −1 ) based on signal to noise ratio of 3 with a 10 µL injection volume allowing direct determination of the compounds in blood and serum (after protein precipitation) at therapeutically realistic concentrations.
Stephen F Donovan - One of the best experts on this subject based on the ideXlab platform.
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lewisite metabolites in urine by solid phase extraction dual column reversed phase liquid chromatography isotope dilution tandem mass spectrometry
Journal of Analytical Toxicology, 2016Co-Authors: Jason Palcic, Janet S Jones, Lindsay E Flagg, Stephen F Donovan, Redentor A Salonga, Walter E Mock, Victor S AsirvathamAbstract:: Lewisite (2-chlorovinyldichloroarsine) is a chemical warfare agent developed during World War I. A quantitative method using solid phase extraction (SPE) followed by dual column liquid chromatography (LC)-isotope dilution tandem mass spectrometry (MS-MS) was developed for the determination of (2-chlorovinyl)arsonic acid (CVAOA), a metabolite of Lewisite, in human urine. The sample was treated with hydrogen peroxide to oxidize any (2-chlorovinyl)arsonous acid (CVAA) that remained in the trivalent Arsenic oxidation state. There was 1.19% (Arsenic purity) of bis-(2-chlorovinyl)arsinic acid (BCVAOA), a minor Lewisite metabolite, in the stock CVAA material. The high-throughput method qualitatively assessed BCVAOA simultaneously utilizing normal-phase silica SPE followed by reversed-phase C18 LC for an orthogonal separation. The chromatographic method results in a 5.8-min cycle time with adequate retention (k' = 2.4) of CVAOA. The mass spectrometer was operated in positive electrospray ionization mode with quantitative m/z 186.9→61.0 and confirmation 186.9→91.0 mass transitions. This selective method demonstrated linearity, accuracy and reproducibility for the clinically relevant calibration range (25-3,200 µg/L as CVAA). The method detection limit was 3.3 µg/L as CVAA from a 10 µL injection. This LC-MS-MS emergency response method has a throughput of >240 samples (2.5 extracted 96-well plates) per day.
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lewisite exposure biomarkers in urine by liquid chromatography inductively coupled plasma tandem mass spectrometry with an accelerated matrix matched stability study
Journal of Analytical Atomic Spectrometry, 2015Co-Authors: Jason Palcic, Janet S Jones, Lindsay E Flagg, Stephen F DonovanAbstract:A simple and robust LC-ICP-MS/MS method is described for quantitative analysis of human urine for (2-chlorovinyl)arsonic acid (CVAOA), a metabolite of Lewisite. This method oxidizes (2-chlorovinyl)arsenous acid (CVAA) with the addition of hydrogen peroxide to measure total Lewisite-1 metabolites as CVAOA, with m/z 75 → 91 detection specific for Arsenic. The percentage of CVAA to CVAOA is clinically insignificant, because the amount of CVAA conversion to CVAOA is dependent upon residence time in the body. Once excreted into the urine, conversion of CVAA to CVAOA is dependent upon temperature and oxidative potential of the urine. The method also allowed for qualitative analysis for bis(2-chlorovinyl)arsinic acid (BCVAOA) and (1-chlorovinyl)arsonic acid (gem-CVAOA), minor Lewisite metabolites. Traditional methods have ignored these minor metabolites; the bis-metabolites can comprise ∼30% of total Lewisite metabolites from chemical munitions and must be accounted for in the exposure measurement. The ion-pairing chromatography method results in a 5.73 min injection-to-injection cycle time with adequate retention (k′ = 2.9) of CVAOA. The weighted (1/x2) linear least squares regression results have correlation coefficients (r2 > 0.998) for the clinically relevant calibration range of 50–3500 μg L−1. The selectivity of the method is measured by chromatographic resolution from other common Arsenic compounds that may interfere with the analysis. The 96-well plate preparation of 0.1 mL sample of human urine results in a method detection limit of 2.2 μg L−1. Quantitative results from proficiency testing specimens demonstrate the accuracy (−7.1 to +4.3%) of the method. Quality control data demonstrate inter-analyst precise (3.1 to 3.3%) quantitative results of the method. An accelerated Arrhenius matrix-matched stability study demonstrates Lewisite metabolites are stabile in urine far greater than a year. The trivalent Arsenic, CVAA oxidation half-life is estimated at normal body temperature in vitro at 6.2 days. The combined sample preparation and analysis portions of this emergency response method have a throughput of 250 samples per day.
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Lewisite exposure biomarkers in urine by liquid chromatography – inductively coupled plasma tandem mass spectrometry: with an accelerated matrix-matched stability study
Journal of Analytical Atomic Spectrometry, 2015Co-Authors: Jason Palcic, Janet S Jones, E. Lindsay Flagg, Stephen F DonovanAbstract:A simple and robust LC-ICP-MS/MS method is described for quantitative analysis of human urine for (2-chlorovinyl)arsonic acid (CVAOA), a metabolite of Lewisite. This method oxidizes (2-chlorovinyl)arsenous acid (CVAA) with the addition of hydrogen peroxide to measure total Lewisite-1 metabolites as CVAOA, with m/z 75 → 91 detection specific for Arsenic. The percentage of CVAA to CVAOA is clinically insignificant, because the amount of CVAA conversion to CVAOA is dependent upon residence time in the body. Once excreted into the urine, conversion of CVAA to CVAOA is dependent upon temperature and oxidative potential of the urine. The method also allowed for qualitative analysis for bis(2-chlorovinyl)arsinic acid (BCVAOA) and (1-chlorovinyl)arsonic acid (gem-CVAOA), minor Lewisite metabolites. Traditional methods have ignored these minor metabolites; the bis-metabolites can comprise ∼30% of total Lewisite metabolites from chemical munitions and must be accounted for in the exposure measurement. The ion-pairing chromatography method results in a 5.73 min injection-to-injection cycle time with adequate retention (k′ = 2.9) of CVAOA. The weighted (1/x2) linear least squares regression results have correlation coefficients (r2 > 0.998) for the clinically relevant calibration range of 50–3500 μg L−1. The selectivity of the method is measured by chromatographic resolution from other common Arsenic compounds that may interfere with the analysis. The 96-well plate preparation of 0.1 mL sample of human urine results in a method detection limit of 2.2 μg L−1. Quantitative results from proficiency testing specimens demonstrate the accuracy (−7.1 to +4.3%) of the method. Quality control data demonstrate inter-analyst precise (3.1 to 3.3%) quantitative results of the method. An accelerated Arrhenius matrix-matched stability study demonstrates Lewisite metabolites are stabile in urine far greater than a year. The trivalent Arsenic, CVAA oxidation half-life is estimated at normal body temperature in vitro at 6.2 days. The combined sample preparation and analysis portions of this emergency response method have a throughput of 250 samples per day.
Jason Palcic - One of the best experts on this subject based on the ideXlab platform.
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lewisite metabolites in urine by solid phase extraction dual column reversed phase liquid chromatography isotope dilution tandem mass spectrometry
Journal of Analytical Toxicology, 2016Co-Authors: Jason Palcic, Janet S Jones, Lindsay E Flagg, Stephen F Donovan, Redentor A Salonga, Walter E Mock, Victor S AsirvathamAbstract:: Lewisite (2-chlorovinyldichloroarsine) is a chemical warfare agent developed during World War I. A quantitative method using solid phase extraction (SPE) followed by dual column liquid chromatography (LC)-isotope dilution tandem mass spectrometry (MS-MS) was developed for the determination of (2-chlorovinyl)arsonic acid (CVAOA), a metabolite of Lewisite, in human urine. The sample was treated with hydrogen peroxide to oxidize any (2-chlorovinyl)arsonous acid (CVAA) that remained in the trivalent Arsenic oxidation state. There was 1.19% (Arsenic purity) of bis-(2-chlorovinyl)arsinic acid (BCVAOA), a minor Lewisite metabolite, in the stock CVAA material. The high-throughput method qualitatively assessed BCVAOA simultaneously utilizing normal-phase silica SPE followed by reversed-phase C18 LC for an orthogonal separation. The chromatographic method results in a 5.8-min cycle time with adequate retention (k' = 2.4) of CVAOA. The mass spectrometer was operated in positive electrospray ionization mode with quantitative m/z 186.9→61.0 and confirmation 186.9→91.0 mass transitions. This selective method demonstrated linearity, accuracy and reproducibility for the clinically relevant calibration range (25-3,200 µg/L as CVAA). The method detection limit was 3.3 µg/L as CVAA from a 10 µL injection. This LC-MS-MS emergency response method has a throughput of >240 samples (2.5 extracted 96-well plates) per day.
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lewisite exposure biomarkers in urine by liquid chromatography inductively coupled plasma tandem mass spectrometry with an accelerated matrix matched stability study
Journal of Analytical Atomic Spectrometry, 2015Co-Authors: Jason Palcic, Janet S Jones, Lindsay E Flagg, Stephen F DonovanAbstract:A simple and robust LC-ICP-MS/MS method is described for quantitative analysis of human urine for (2-chlorovinyl)arsonic acid (CVAOA), a metabolite of Lewisite. This method oxidizes (2-chlorovinyl)arsenous acid (CVAA) with the addition of hydrogen peroxide to measure total Lewisite-1 metabolites as CVAOA, with m/z 75 → 91 detection specific for Arsenic. The percentage of CVAA to CVAOA is clinically insignificant, because the amount of CVAA conversion to CVAOA is dependent upon residence time in the body. Once excreted into the urine, conversion of CVAA to CVAOA is dependent upon temperature and oxidative potential of the urine. The method also allowed for qualitative analysis for bis(2-chlorovinyl)arsinic acid (BCVAOA) and (1-chlorovinyl)arsonic acid (gem-CVAOA), minor Lewisite metabolites. Traditional methods have ignored these minor metabolites; the bis-metabolites can comprise ∼30% of total Lewisite metabolites from chemical munitions and must be accounted for in the exposure measurement. The ion-pairing chromatography method results in a 5.73 min injection-to-injection cycle time with adequate retention (k′ = 2.9) of CVAOA. The weighted (1/x2) linear least squares regression results have correlation coefficients (r2 > 0.998) for the clinically relevant calibration range of 50–3500 μg L−1. The selectivity of the method is measured by chromatographic resolution from other common Arsenic compounds that may interfere with the analysis. The 96-well plate preparation of 0.1 mL sample of human urine results in a method detection limit of 2.2 μg L−1. Quantitative results from proficiency testing specimens demonstrate the accuracy (−7.1 to +4.3%) of the method. Quality control data demonstrate inter-analyst precise (3.1 to 3.3%) quantitative results of the method. An accelerated Arrhenius matrix-matched stability study demonstrates Lewisite metabolites are stabile in urine far greater than a year. The trivalent Arsenic, CVAA oxidation half-life is estimated at normal body temperature in vitro at 6.2 days. The combined sample preparation and analysis portions of this emergency response method have a throughput of 250 samples per day.
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Lewisite exposure biomarkers in urine by liquid chromatography – inductively coupled plasma tandem mass spectrometry: with an accelerated matrix-matched stability study
Journal of Analytical Atomic Spectrometry, 2015Co-Authors: Jason Palcic, Janet S Jones, E. Lindsay Flagg, Stephen F DonovanAbstract:A simple and robust LC-ICP-MS/MS method is described for quantitative analysis of human urine for (2-chlorovinyl)arsonic acid (CVAOA), a metabolite of Lewisite. This method oxidizes (2-chlorovinyl)arsenous acid (CVAA) with the addition of hydrogen peroxide to measure total Lewisite-1 metabolites as CVAOA, with m/z 75 → 91 detection specific for Arsenic. The percentage of CVAA to CVAOA is clinically insignificant, because the amount of CVAA conversion to CVAOA is dependent upon residence time in the body. Once excreted into the urine, conversion of CVAA to CVAOA is dependent upon temperature and oxidative potential of the urine. The method also allowed for qualitative analysis for bis(2-chlorovinyl)arsinic acid (BCVAOA) and (1-chlorovinyl)arsonic acid (gem-CVAOA), minor Lewisite metabolites. Traditional methods have ignored these minor metabolites; the bis-metabolites can comprise ∼30% of total Lewisite metabolites from chemical munitions and must be accounted for in the exposure measurement. The ion-pairing chromatography method results in a 5.73 min injection-to-injection cycle time with adequate retention (k′ = 2.9) of CVAOA. The weighted (1/x2) linear least squares regression results have correlation coefficients (r2 > 0.998) for the clinically relevant calibration range of 50–3500 μg L−1. The selectivity of the method is measured by chromatographic resolution from other common Arsenic compounds that may interfere with the analysis. The 96-well plate preparation of 0.1 mL sample of human urine results in a method detection limit of 2.2 μg L−1. Quantitative results from proficiency testing specimens demonstrate the accuracy (−7.1 to +4.3%) of the method. Quality control data demonstrate inter-analyst precise (3.1 to 3.3%) quantitative results of the method. An accelerated Arrhenius matrix-matched stability study demonstrates Lewisite metabolites are stabile in urine far greater than a year. The trivalent Arsenic, CVAA oxidation half-life is estimated at normal body temperature in vitro at 6.2 days. The combined sample preparation and analysis portions of this emergency response method have a throughput of 250 samples per day.
Georg Raber - One of the best experts on this subject based on the ideXlab platform.
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determination of the trypanocidal drug melarsoprol and its conversion products in biological fluids with hplc icpms esms
Talanta, 2013Co-Authors: Georg Raber, Thomas Raber, Reingard Raml, Manuela Murko, Christoph Magnes, Kevin A. FrancesconiAbstract:Abstract Although melarsoprol, an organoArsenic compound, is widely used for the treatment of trypanosomiasis (human African sleeping sickness), very little is known about its fate in the human body, its active metabolites passing the blood–brain barrier and the mode of action. Previous pharmacological studies based on the determination of melarsoprol by HPLC–UV or by a bioassay method produced different results. We report a HPLC–ICPMS method suitable for determining melarsoprol and its metabolites in biological fluids. The Arsenic selective capability of the method allowed the quantitative measurement of melarsoprol and two Arsenic-containing conversion products produced when melarsoprol was incubated with human serum and blood. The major product was identified as melarsen [4-[(4,6-diamino-1,3,5-triazin-2-yl)amino]phenyl]arsonic acid by HPLC/electrospray MS, and by accurate mass measurements. Investigations about the stability of melarsoprol in serum showed that within 30 h about 10% of melarsoprol is converted to melarsen. In blood, however, most of the melarsoprol was bound to proteins and only 1% was converted to melarsen after 30 hours. The limit of detection for melarsoprol and its conversion products were in the range of 1 µg As L −1 (13 nmol As L −1 ) based on signal to noise ratio of 3 with a 10 µL injection volume allowing direct determination of the compounds in blood and serum (after protein precipitation) at therapeutically realistic concentrations.
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Determination of the trypanocidal drug melarsoprol and its conversion products in biological fluids with HPLC-ICPMS/ESMS.
Talanta, 2013Co-Authors: Georg Raber, Thomas Raber, Reingard Raml, Manuela Murko, Christoph Magnes, Kevin A. FrancesconiAbstract:Abstract Although melarsoprol, an organoArsenic compound, is widely used for the treatment of trypanosomiasis (human African sleeping sickness), very little is known about its fate in the human body, its active metabolites passing the blood–brain barrier and the mode of action. Previous pharmacological studies based on the determination of melarsoprol by HPLC–UV or by a bioassay method produced different results. We report a HPLC–ICPMS method suitable for determining melarsoprol and its metabolites in biological fluids. The Arsenic selective capability of the method allowed the quantitative measurement of melarsoprol and two Arsenic-containing conversion products produced when melarsoprol was incubated with human serum and blood. The major product was identified as melarsen [4-[(4,6-diamino-1,3,5-triazin-2-yl)amino]phenyl]arsonic acid by HPLC/electrospray MS, and by accurate mass measurements. Investigations about the stability of melarsoprol in serum showed that within 30 h about 10% of melarsoprol is converted to melarsen. In blood, however, most of the melarsoprol was bound to proteins and only 1% was converted to melarsen after 30 hours. The limit of detection for melarsoprol and its conversion products were in the range of 1 µg As L −1 (13 nmol As L −1 ) based on signal to noise ratio of 3 with a 10 µL injection volume allowing direct determination of the compounds in blood and serum (after protein precipitation) at therapeutically realistic concentrations.
Manuela Murko - One of the best experts on this subject based on the ideXlab platform.
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Dose and Diet - Sources of Arsenic Intake in Mouse in Utero Exposure Scenarios.
Chemical Research in Toxicology, 2018Co-Authors: Manuela Murko, David J Thomas, Brittany Elek, Miroslav Styblo, Kevin A. FrancesconiAbstract:In humans, early life exposure to inorganic Arsenic is associated with adverse health effects. Inorganic Arsenic in utero or in early postnatal life also produces adverse health effects in offspring of pregnant mice that consumed drinking water containing low part per billion levels of inorganic Arsenic. Because aggregate exposure of pregnant mice to inorganic Arsenic from both drinking water and food has not been fully evaluated in experimental studies, quantifying Arsenic exposure of the developing mouse is problematic. Here, we determined levels of total Arsenic and Arsenic species in natural ingredient rodent diets that are composed of many plant and animal-derived foodstuffs and in a purified ingredient rodent diet that is composed of a more restricted mixture of foodstuffs. In natural ingredient diets, total Arsenic levels ranged from ∼60 to ∼400 parts per billion, and in the purified ingredient diet, total Arsenic level was 13 parts per billion. Inorganic Arsenic was the predominant Arsenic species...
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determination of the trypanocidal drug melarsoprol and its conversion products in biological fluids with hplc icpms esms
Talanta, 2013Co-Authors: Georg Raber, Thomas Raber, Reingard Raml, Manuela Murko, Christoph Magnes, Kevin A. FrancesconiAbstract:Abstract Although melarsoprol, an organoArsenic compound, is widely used for the treatment of trypanosomiasis (human African sleeping sickness), very little is known about its fate in the human body, its active metabolites passing the blood–brain barrier and the mode of action. Previous pharmacological studies based on the determination of melarsoprol by HPLC–UV or by a bioassay method produced different results. We report a HPLC–ICPMS method suitable for determining melarsoprol and its metabolites in biological fluids. The Arsenic selective capability of the method allowed the quantitative measurement of melarsoprol and two Arsenic-containing conversion products produced when melarsoprol was incubated with human serum and blood. The major product was identified as melarsen [4-[(4,6-diamino-1,3,5-triazin-2-yl)amino]phenyl]arsonic acid by HPLC/electrospray MS, and by accurate mass measurements. Investigations about the stability of melarsoprol in serum showed that within 30 h about 10% of melarsoprol is converted to melarsen. In blood, however, most of the melarsoprol was bound to proteins and only 1% was converted to melarsen after 30 hours. The limit of detection for melarsoprol and its conversion products were in the range of 1 µg As L −1 (13 nmol As L −1 ) based on signal to noise ratio of 3 with a 10 µL injection volume allowing direct determination of the compounds in blood and serum (after protein precipitation) at therapeutically realistic concentrations.
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Determination of the trypanocidal drug melarsoprol and its conversion products in biological fluids with HPLC-ICPMS/ESMS.
Talanta, 2013Co-Authors: Georg Raber, Thomas Raber, Reingard Raml, Manuela Murko, Christoph Magnes, Kevin A. FrancesconiAbstract:Abstract Although melarsoprol, an organoArsenic compound, is widely used for the treatment of trypanosomiasis (human African sleeping sickness), very little is known about its fate in the human body, its active metabolites passing the blood–brain barrier and the mode of action. Previous pharmacological studies based on the determination of melarsoprol by HPLC–UV or by a bioassay method produced different results. We report a HPLC–ICPMS method suitable for determining melarsoprol and its metabolites in biological fluids. The Arsenic selective capability of the method allowed the quantitative measurement of melarsoprol and two Arsenic-containing conversion products produced when melarsoprol was incubated with human serum and blood. The major product was identified as melarsen [4-[(4,6-diamino-1,3,5-triazin-2-yl)amino]phenyl]arsonic acid by HPLC/electrospray MS, and by accurate mass measurements. Investigations about the stability of melarsoprol in serum showed that within 30 h about 10% of melarsoprol is converted to melarsen. In blood, however, most of the melarsoprol was bound to proteins and only 1% was converted to melarsen after 30 hours. The limit of detection for melarsoprol and its conversion products were in the range of 1 µg As L −1 (13 nmol As L −1 ) based on signal to noise ratio of 3 with a 10 µL injection volume allowing direct determination of the compounds in blood and serum (after protein precipitation) at therapeutically realistic concentrations.