Pharmacokinetics (ADME), dose-response and pharmacokinetic modeling of bromate in F344 rats
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Bromate (BrO3-), a toxic by-product formed during ozonation of ground or source water containing bromide (Br-). The reactivity of BrO3- with the biological reductants (especially thiols) results in a substantial reduction to Br- at low doses, which leads to exhibition of non-linear pharmacokinetics in F344 rats. To test this hypothesis, BrO3- acute dosing studies (0.1 to 20 mg/kg KBrO3) administered as either IV bolus or oral gavage were conducted in female F344 rats. Analysis of BrO3- pharmacokinetic parameters revealed that disproportionate increase in peak concentration (Cmax or C0) and the area under curve (AUC) of plasma BrO3- were in correlation with the increased plasma BrO3- clearance for the doses 0.5 and 1 mg/kg, compared to 0.1 mg/kg KBrO3. BrO3- was eliminated from the body in a first order fashion with an elimination rate constant (Ke) of 0.03 min-1, and plasma half-life of ~23 min. The oral bioavailability (F) of BrO3- is ~35 %, indicates the occurrence of high pre systemic reduction of BrO3- in rats. The plasma half-life for BrO3- after oral gavage is ~30 min. for doses up to 2.5 mg/kg KBrO3. However, the increases in plasma BrO3- half-life following the oral administration of 20 mg/kg KBrO3 was in correlation with the decreased elimination rate constant (Ke) from 0.03 to 0.016 min-1 and increased volume of distribution (Vd) from 0.87 to 1.46 L/kg. The rate of BrO3- reduction was higher compared to the rate of Br- formation from BrO3- both in vitro and in vivo. The incubation of 0-2840 μM BrO3- in rat blood in vitro showed that BrO3- degrades in a rapid initial and slow secondary manner. Loss of BrO3- during both phases was accompanied by increases in Br- concentrations indicating that the BrO3- loss was due to its reduction. A very small amount ~6% was recovered as BrO3- in urine following administration of a single dose of 8.1 mg KBrO3/kg as an oral gavage. Br- elimination from BrO3- over the first 48 hours was 18% lower than it was eliminated from an equi molar single dose of Br-, 5 mg KBr/kg (15.5 ± 1.6 vs. 18.8 ±1.2 μmol/kg, respectively). The cumulative excretion of Br- from KBr vs. KBrO3 was equivalent 72 hours after administration. Moreover, the deficits in total BrO3- recovery raises the possibility that some brominated biochemicals may be produced in vivo, which slowly gets metabolized and eliminated from the body.