PHARMACOKINETICS OF INTRACEREBROVENTRICULAR TBUOOH IN YOUNG-ADULT ANDMATURE MICE

This in vivo study compared the pharmacokinetics of intracerebroventri cularly administered tertiary butylhydroperoxide (tBuOOH) (109.7 mg/kg ) among six different brain regions in two age groups of mice (2- and 8-mo-old mice). Brains were dissected at 11 time-points ranging from 0 .5-60 min. Pharmacokinetics parameters did not differ between the two age groups. This demonstrates that previously reported age-related dif ferences in tBuOOH toxicity may not be owing to pharmacokinetic differ ences between the two age groups. Differences were found when comparin g the pharmacokinetics of tBuOOH among the various brain regions. Area under the curve (AUC) values were highest in the striatum and thalamu s, and lowest in the cerebellum. The half-life of tBuOOH varied widely among the regions with the longest half-lives in the cortex and hippo campus, and the shortest in the striatum and cerebellum. The oxidation of glutathione and the induction of DNA damage are critical aspects o f tBuOOH toxicity. These data show that region-dependent differences i n toxicity reported previously may result from factors, such as tBuOOH -induced glutathione oxidation and DNA damage.