Dichloroacetic acid

Health surveillance data

Administrative data

Endpoint:

health surveillance data

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Publication peer reviewed

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1985

Materials and methods

Study type:

human medical data

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Dichloroacetic acid

EC Number:

201-207-0

EC Name:

Dichloroacetic acid

Cas Number:

79-43-6

Molecular formula:

C2H2Cl2O2

IUPAC Name:

2,2-dichloroacetic acid

Details on test material:

- Name of test material (as cited in study report): sodium dichloroacetate (DCA)
The sodium salt of DCA we used was initially of unconfirmed identity and purity. Thus we first studied it by nuclear magnetic resonance spectroscopy, infrared spectroscopy, and elemental analysis. The formation of its methyl ester when treated with boron trifluoride (BF3)/methanol was followed by comparison with authentic methyldichloroacetate by gas chromatography.
The drug was dissolved in isotonic saline solution at 100 mg/mL, adjusted to approximately pH 5.2 with sodium monobasic and dibasic phosphate injectable solution, and sterilized by an autoclave ( 121° for 20 min) after passage through a 0.22-µm filter. Samples of the injection solution were assayed by gas chromatography.
Limulus lysate testing was also performed to rule out the presence of pyrogens in the final parenteral product.

Method

Type of population:

general

Details on study design:

Metabolism study, 50 mg dichloroacetic acid / kg bw, i.v. or p.o.

Results and discussion

Results:

Oral or intravenous administration of 50 mg Dichloroacetate (DCA)/kg bw to healthy volunteers resulted in excretion of oxalate and DCA as the main metabolites. In the urine, 5% of the administered dose was found. The half-life of DCA in plasma after a single dose was between 0.5 and 2 hours. Apparently, only very small amounts of DCA were bound to plasma proteins. After repeated administration, the half-life increased several-fold (possibly as a result of enzyme inhibition by DCA or metabolites).

The DCA sample was shown to be of stated identity by nuclear magnetic resonance spectroscopy (which showed the CHCl2 grouping), by infra-red spectroscopy (which showed the C―Cl, COOH, and C =O groupings), and by elemental analysis (which agreed with the putative formula). The material was converted to a methyl ester by reaction with BF3/methanol. Injection solutions typically assayed at 99.5% of stated concentration, indicating >99% purity.
DCA is metabolized by rat liver to glyoxylate, which is then converled to oxalate. Ours was the first attempt to relate oxalate excretion to DCA dosing in man, and we could find no evidence in the literature that the putative DCA metabolites do not interfere with the DCA assay. We prepared a series of plasma samples containing DCA (100 µg/mL) and varioils quantities (10, 100, and 1000 µg/mL) of oxalic, glyoxylic, and glycolic acids. There were no interfering peaks after gas chromatography; DCA concentrations varied from 97.5 to 107.2 µg/mL, with no relationship between contaminant and DCA concentration.
Our seven male and four female subjects were unevenly distributed over the three dose levels with respect to sex, but the difference was not significant (x2 = 5.04). In each subject throughout the study, DCA concentrations rose during each infusion and fell after the end of each infusion, declining towards or to zero after the last dose. There was much variation within the data, even among subjects receiving the same dose. The AUC for each set of data from zero to infinity was linearly related to dose; the Pearson correlation coefficient for this relationship was r = 0.72. In the basal (fasted overnight) state, mean blood glucose concentration was 80 ± 2.2 mg% (mean ± SE). Blood glucose levels increased transiently after each meal and then returned to baseline. The mean maximum fall in glucose concentration was 8% and occurred 24 hr after the initial DCA infusion and 10 to 12 hr after the last meal.
Each DCA regimen induced marked and sustained falls in blood lactate levels. At doses of 10 and 25 mg/kg, lactate levels fell a maximum of about 50%. After the 50-mg/kg doses, lactate levels fell 70% and were more likely to remain reduced for 24 hr after this dose than after the lower doses. There was a clear intersubject relationship between 24-hr lactate level and 24-hr plasma DCA concentration. In four subjects in whom the 24-hr DCA plasma concentration was zero, the mean change in 24-hr lactate levels from baseline was 2%. In four subjects in whom the 24-hr DCA level was >0 but <100 mg/kg, the corresponding mean fall in lactate level was 22%. In four subjects in whom the 24-hr DCA concentration was > 100 mg/kg, the corresponding mean fall in lactate level was 53%. The correlation coefficient for the linear relationship between 24-hr lactate and 24-hr DCA levels was r = -0.58.
The expected postprandial rise in circulating lactate levels after the initial 10- and 25-mg/kg infusions was almost completely absent after the 50-mg/kg doses.
DCA dosing led to a dose-dependent increase in oxalate excretion. The correlation coefficient for this linear relationship was r = 0. 767, and the linear relationship extrapolated to a normal oxalate excretion (29.5 mg/gm creatinine) at a drug dose of zero. With repeated doses of 50 mg/kg DCA, mean 24-hr urinary oxalate excretion was approximately 200 mg/gm creatinine-about 700% the daily excretion rate for healthy subjects at our institution.
Blood pressure and pulse remained stable. Subjects receiving 10 or 25 mg/kg DCA did not have any undesirable effects. Three subjects receiving 50 mg/kg DCA had mild drowsiness after the second or third infusion that lasted several hours after the final dose.
The fourth subject at this dose noted moderate sedation and temporary nausea on standing; sedation persisted for approximately 24 hr after the final dose. Two subjects receiving 50 mg/kg complained of pain at the infusion site, apparently caused by inadequate buffering of the infusion solutions. Tenderness and induration along the affected vein gradually resolved over approximately 2 wk .
The mean DCA t1/2 rose from 63.3 min (range 15.0 to 112.2 min) after the first dose to 374.0 min (range 37.8 to 1386.0 min) after the fifth dose. In all cases but one, the t1/2 of the fifth dose was longer than that of the first dose; the difference in the means was significant. Mean rises in DCA concentration during the first to the fifth infusions were 106.9, 86.6, 86.9, 75.5, and 116.7 µg/mL; analysis of variance did not indicate a significant trend with time. Table I also lists mean apparent volume of distribution data calculated after each of the five doses. There were no significant differences. Overall mean apparent volume of distribution of DCA was 0.30 L/kg (range 0.09 to 0.60 L/kg). Mean instantaneous rates of elimination of DCA at the 30-min time points after each infusion were 1393.8 ± 300.6, 1089.1 ± 169.5, 881.7 ± 250.9, 950.2 ± 282.2, and 723.8 ± 154.6 mg/kg/hr (mean ± SE). The downward trend in these figures was significant (analysis of variance). In every case, Cpt at the 30-min point rose from the first to the fifth dose.

Applicant's summary and conclusion

Executive summary:

Eleven healthy subjects received five doses of intravenous sodium dichloroacetate (DCA) at 2-hr intervals.

Determinations of DCA in plasma and of lactate and glucose in blood were made at various times until 24 hr after starring the first infusion. Twenty-four-hour urinary oxalate excretion was also measured.

DCA levels rose and fell during and after each dose, with higher levels induced by higher doses. Lactate levels fell as the result of DCA treatment, with greater falls after higher doses, and returned to normal after 24 hr at the two lower dose levels but not at the level of 50 mg/kg. Lactate levels did not change parallel to changes in DCA levels. Only the doses of 50 mg/kg prevented postprandial rises in lactate levels. Blood glucose levels were not altered. The mean DCA t1/2 after the initial doses was 63.3 min (range 15.0 to 112.2 min), while that after the final doses was 374.0 min (range 37.8 to 1386.0 min).

The AUC and the DCA-induced increase in urinary oxalate excretion were linearly related to dose. Mean DCA apparent volume of distribution was 0.30 L/kg (range 0.09 to 0.60 L/kg).