Arsenic Speciation in Urine from Acute Promyelocytic Leukemia Patients undergoing Arsenic Trioxide Treatment

Abstract

Arsenic has been used successfully in clinical trials for treating acute promyelocytic leukemia (APL). Although sublethal doses of inorganic arsenic are used, little is known about the pharmacokinetics and metabolism of the high levels of arsenic in APL patients. To fill this important gap, this study describes the speciation of arsenic in urine from four APL patients treated with arsenic. Each patient was injected daily with an arsenite (As(III)) solution that contained 10 mg of As(2)O(3) precursor. Speciation analysis of the patient urine samples collected consecutively for 48 h, encompassing two intravenous injections of arsenic, revealed the presence of monomethylarsonous acid (MMA(III)), dimethylarsinous acid (DMA(III)), monomethylarsonic acid (MMA(V)), and dimethylarsinic acid (DMA(V)). The intermediate methyl arsenic metabolites, MMA(III) and DMA(III), were detected in most urine samples from all of the patients when a preservative, diethyldithiocarbomate, was added to the urine samples to stabilize these trivalent arsenic species. The major arsenic species detected in the urine samples from the patients were As(III), MMA(V), and DMA(V), accounting for >95% of the total arsenic excreted. The relative proportions of As(III), As(V), MMA(V), and DMA(V) in urine samples collected 24 h after the injections of As(III) were 27.6 +/- 6.1, 2.8 +/- 2.0, 22.8 +/- 8.1, and 43.7 +/- 13.3%, respectively. The relatively lower fraction of the methylated arsenic species in these APL patients under arsenic treatment as compared with that from the general population exposed to much lower levels of arsenic suggests that the high levels of As(III) inhibit the methylation of arsenic (inhibits the formation of methyl arsenic metabolites). The arsenic species excreted into the urine accounted for 32-65% of the total arsenic injected. These results suggest that other pathways of excretion, such as through the bile, may play an important role in eliminating (removing) arsenic from the human body when challenged by high levels of As(III).

Intraindividual Variability in Arsenic Methylation in a U.S. Population

“…Although the pentavalent forms of monomethylarsonate and dimethylarsinate seem more readily excreted than inorganic arsenic, several studies have shown that MMA3 is more acutely toxic than dimethylarsinate or inorganic arsenic (25)(26)(27)(28)(29)(30)(31)(32). Only a few studies have investigated the presence of MMA3 in nonchelated humans (45,57,58). In a study of six subjects from an arsenic-exposed region in Mexico, the proportion of urinary MMA3 was 0.9%, whereas the proportions of inorganic arsenic, MMA5, DMA3, and DMA5 were 23.5%, 18.5%, 8.8%, 48.2%, respectively (45).…”

Application of Arsenic Trioxide Therapy for Patients with Leukaemia

“…These observations together with our recent study [31] suggest that biomethylation may in fact generate potentially cytocidal metabolites that may significantly contribute to the therapeutic effect as well as side effects of ATO in APL patients. Indeed, MAs III and DMAs III have been detected in the urine of APL patients undergoing ATO treatment [167] and healthy individuals who have drunk water containing inorganic arsenic [155,168], and in human hepatoma (HepG2) cells exposed to As III [155]. Therefore, elucidation of arsenic metabolism is very important for achieving better therapeutic effects, and is critical in reducing side effects of ATO.…”

Impact of arsenic trioxide in the treatment of acute promyelocytic leukemia

“…25 Measurements of ATO metabolites in urine have led to differing results across several studies, ranging from 1-8 to 19% or 32À65%. [24][25][26][27] Independently of this unexplained broad range, the results indicate that other elimination mechanisms, such as bile and feces, must have a role in the excretion of high arsenic doses. In a study of adult cancer patients with varying degrees of renal dysfunction, systemic exposure of arsenic and its methylated metabolites following standard dosing of ATO was increased.…”