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dc.contributor.authorKolisetty, Narendrababu
dc.date.accessioned2014-03-04T20:36:14Z
dc.date.available2014-03-04T20:36:14Z
dc.date.issued2012-08
dc.identifier.otherkolisetty_narendrababu_201208_phd
dc.identifier.urihttp://purl.galileo.usg.edu/uga_etd/kolisetty_narendrababu_201208_phd
dc.identifier.urihttp://hdl.handle.net/10724/28312
dc.description.abstractBromate (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.
dc.languageeng
dc.publisheruga
dc.rightspublic
dc.subjectBromate
dc.subjectAbsorption
dc.subjectDisposition
dc.subjectReaction products
dc.subjectRat
dc.titlePharmacokinetics (ADME), dose-response and pharmacokinetic modeling of bromate in F344 rats
dc.typeDissertation
dc.description.degreePhD
dc.description.departmentPharmaceutical and Biomedical Sciences
dc.description.majorPharmacy
dc.description.advisorBrian Cummings
dc.description.committeeBrian Cummings
dc.description.committeeCatherine White
dc.description.committeeJeffrey Fisher
dc.description.committeeJames Bruckner
dc.description.committeeRobert D. Arnold


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