title: Exceptions in patterns of arsenic compounds in urine of acute promyelocytic leukaemia patients treated with As2O3.
abstract: Arsenic trioxide (As(III) in solution) has been shown to be the most active single agent in combating acute promyelocytic leukemia (APL). It is metabolized and excreted via urine as monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) and As(V), along with excess As(III). In our study eight APL patients were treated (intravenously) with 0.15 mg As2O3/kg/day. During the therapy As(III) and its metabolites were followed in pre- and post-infusion urine using HPLC for separation followed by on-line detection using hydride generation-atomic fluorescence spectrometry. Five patients had a normal excretion pattern of residual arsenic compounds in morning pre-infusion urine, with 15-25% of As(III), 35-55% of DMA, 25-30% of MMA and 1-5% of As(V), while three patients showed unexpected exceptions from typical excretion patterns of arsenic compounds (i) a high DMA/MMA ratio (factor 5.3), (ii) severe As(III) oxidation (10.2% As(III) converted to As(V)) or (iii) the presence of an excessive amount of As(III) (average 30.4% of total arsenic). Intriguing was the occurrence of post-infusion oxidation of As(III) to As(V) observed in almost all patients and being especially high (>40%) in patient with increased residual As(V). Results indicate that arsenic metabolites patterns can be unpredictable. Observed high levels of un-metabolised As(III) are a warning signal for side effects and for routine determination of arsenic metabolites during first days of treatment. High or low percentages of MMA or DMA did not show any observable effect on treatment results, while clear presence of post-infusion As(V) supports theoretical claims of in vivo oxidation (detoxification) of As(III) to As(V) associated with various metabolic processes.
authors.affiliation: Jožef Stefan Institute, Jamova 39, 1000, Ljubljana, Slovenia. zdenka.slejkovec@ijs.si.
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Šlejkovec
authors.affiliation: University Medical Centre Ljubljana, Zaloška 7, 1000, Ljubljana, Slovenia.
authors.forename: Helena
authors.initials: H
authors.lastname: Podgornik
authors.affiliation: University Medical Centre Ljubljana, Zaloška 7, 1000, Ljubljana, Slovenia.
authors.forename: Peter
authors.initials: P
authors.lastname: Černelč
authors.affiliation: Jožef Stefan Institute, Jamova 39, 1000, Ljubljana, Slovenia.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Falnoga
mesh_terms: D000328:Adult; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000652:urine*; D002101:Cacodylic Acid / Q000652:urine*; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000473:pathology / Q000652:urine; D008297:Male; D008875:Middle Aged; D010087:Oxides / Q000008:administration & dosage
chemical_list: D001152:Arsenicals; D010087:Oxides; D002101:Cacodylic Acid; C020300:monomethylarsonic acid; D000077237:Arsenic Trioxide
keywords: Acute promyelocytic leukemia; Arsenic trioxide; Biotransformation; Metabolites; Speciation; Urine