PNNL

Abstract

Pharmacokinetics of halogenated acetic acid (HAA) mixtures in naïve and GSTzeta depleted rats was investigated. Rats were administered orally or i.v. to Mixture-1 (monobromo- dichloro-, chlorodibromo-, tribromo- acetic acids) or Mixture-2 (bromochloro-, dibromo-, trichloro- bromodichloro- acetic acids) at a dose of 25 µmol/kg HAA and blood samples collected up to 36 h. GSTzeta depleted rats were also orally dosed with each mixture and euthanized at 0.25, 0.5, 1, 2 and 4 h to determine tissue distribution. In Mixture-1, GSTzeta depletion only affected the pharmacokinetics of DCAA, which increased the eliminaiton t½ from 9 min to 1.3 h. After oral administration, DCAA exhibited a complex time-course plasma profile with secondary peaks appearing long after completion of the initial absorption phase. This phenomenon coincided with elevated DCA levels in the lower portion of the GI tract compared to CDBAA and TBAA. For Mixture-2, all di-HAAs were eliminated extremely rapidly from plasma in both naïve and GSTzeta depleted animals (t½ was 4-11 min in naïve and 11-24 min in GSTzeta depleted rats), t½ of BDCAA and TCAA was 3.5 and 12 h in naïve and 2.3 and 7.5 h in GSTzeta depleted rats. The primary difference in the pharmacokinetics among HAAs when administered as mixture was the total body clearance (Clb) which was reduced compared to after individual administration. These results suggest competitive interactions between tri- and di-HAAs beyond what would be predicted from individual HAA studies. For di-HAAs, the total dose is important as clearance is dose dependent due to competition for GSTzeta. When considering HAAs dosimetry, importance should be placed on both the components of the mixture and prior exposure history to di-HAAs.