Oxalic acid excretion after intravenous ascorbic acid administration
Introduction
Oxalic acid is a major end product of ascorbic acid oxidation, and it has the potential to crystallize as calcium oxalate in the urinary space. An oral dose of 500 mg ascorbic acid modestly increases urinary oxalic acid excretion and could theoretically increase the risk of stone formation in susceptible people [1], [2], [3], [4]. The rate limitation of intestinal ascorbic acid transport makes it unlikely that oral doses greater than 500 mg/d will increase oxalic acid excretion and stone risk proportionately [5], [6], but intravenous administration bypasses this barrier. In an early study, 44% of the radioactivity in an intravenous dose of 14C-ascorbic acid was recovered in the urine as oxalic acid [7]. In the setting of renal dysfunction, acute oxalate nephropathy has been reported after intravenous ascorbic acid administration [8], [9], [10]. Increased urinary oxalic acid excretion has also been reported in connection with parenteral nutrition solutions that included 200 to 500 mg/d of ascorbic acid [11], [12]. Much larger doses than this have been administered therapeutically in recent years [13], [14], [15], [16], but without any information about the associated rate of oxalic acid excretion.
Barriers to the study of oxalic acid formation during ascorbic acid treatment are interference with the analysis by high ascorbic acid concentrations and in vitro conversion of excreted ascorbic acid to oxalic acid in the collection vessel or during storage or analysis [2], [17], [18], [19], [20]. In this study, we overcame these barriers by immediately acidifying urine specimens and promptly storing them at very low temperature and by developing a gas chromatography mass spectrometry (GC-MS) technique that avoids alkaline extraction [21], which oxidizes ascorbic acid to oxalic acid [2]. This method was then used to analyze the pattern of urinary oxalic acid excretion in patients participating in a clinical trial of high-dose intravenous ascorbic acid as cancer therapy.
Section snippets
Study participants and clinical trial design
Urinary oxalic acid excretion was measured in 11 men and 5 women (age, 58 ± 17 years; weight, 69 ± 18 kg; mean ± SD) participating in a phase I clinical trial of intravenous ascorbic acid in advanced cancer [22]. All participants in the trial had good functional status, were biochemically screened for glucose-6-phosphate dehydrogenase deficiency—which is associated with hemolytic episodes after high-dose ascorbic acid infusions [17]—had undergone an abdominal x-ray examination to screen for
Method validation
As shown in Fig. 1, the SIM chromatograms for m/z 261 and 263 were well characterized, and a conventional calibration curve relating amounts of [12C2]- and [13C2]-oxalic acid to the measured intensity ratios of m/z 261 to m/z 263 was easily constructed. Recovery of physiologic amounts of oxalic acid added to 6 normal urine samples was 100% ± 6.9% (mean ± SD). Acid-only extraction, as used here, was compared with the conventional method involving base and acid extraction. Addition of ascorbic
Discussion
This article describes a novel method to analyze oxalic acid accurately in the presence of very high concentrations of ascorbic acid and its use to determine the urinary oxalic acid excretion profiles of patients administered very large intravenous doses of ascorbic acid.
Accurate oxalic acid analysis in the presence of ascorbic acid requires a strongly acid environment and sample storage at low temperature to prevent in vitro oxidation of ascorbic acid to oxalic acid. Acid conditions are also
Acknowledgment
This study was funded by a grant from the Lotte and John Hecht Memorial Foundation and from Research Resource Program Grant PRG-80160 from the Canadian Institutes of Health Research. WHM is a Chercheur National of the Fonds de la Recherche en Santé du Québec. ML is supported by the Intramural Research Program, National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases.
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