Effects of Febuxostat on Autistic Behaviors and Computational Investigations of Diffusion and Pharmacokinetics

Autism spectrum disorder (ASD) is a lifelong disability that has seen a rise in prevalence from 1 in 150 children to 1 in 59 between 2000 and 2014. Patients show behavioral abnormalities in the areas of social interaction, communication, and restrictive and repetitive behaviors. As of now, the exact cause of ASD is unknown and literature points to multiple causes. The work contained within this dissertation explored the reduction of oxidative stress in brain tissue induced by xanthine oxidase (XO). Febuxostat is a new FDA approved XO-inhibitor that has been shown to be more selective and potent than allopurinol in patients with gout. The first study developed a computational model to calculate an effective diffusion constant (Deff) of lipophilic compounds, such as febuxostat, that can cross endothelial cells of the blood-brain barrier (BBB) by the transcellular pathway. In the second study, male juvenile autistic (BTBR) mice were treated with febuxostat for seven days followed by behavioral testing and quantification of oxidative stress in brain tissue compared to controls. Results of the first study showed that the lipophilic tracer chosen, as a substitute for febuxostat, could be modeled under the assumption of passive diffusion while experimental controls did not fit this model. The second study revealed no significant differences between BTBR mice that received febuxostat or the drug vehicle in both behavioral testing and quantification of oxidative stress in brain tissue. In the final study, of the four models proposed, one model was selected as the most plausible that considered transport into the CNS. As there is currently no literature surrounding tissue and organ ADME for febuxostat the final proposed model would need to be updated as new information becomes available.