Collections > Electronic Theses and Dissertations > A Multi-Factorial Approach to Understanding and Predicting Brain Exposure to Pharmacologic Agents

Development of effective neurotherapeutics is limited by an inability to deliver sufficient drug mass to sites of action within the brain, due to specialized structural and functional characteristics of the interface between the CNS and the systemic circulation (the blood-brain barrier; BBB). A potential solution to this critical challenge involves chemical inhibition of P-glycoprotein (P-gp), an important barrier transporter expressed at the blood-brain interface that attenuates brain uptake of numerous CNS-targeted agents. To determine how modulation of brain exposure to a model P-gp substrate could impact pharmacologic response, the relationship between response of a human brain tumor cell line and exposure to the antineoplastic paclitaxel was explored in vitro. Mathematical modeling of these data demonstrated that substantial inhibition of BBB P-gp could significantly reduce the paclitaxel dose required to elicit a meaningful antitumor effect. As P-gp is expressed in many tissues, selective inhibition of BBB P-gp is desirable for increasing brain partitioning of P-gp substrates. A brain-targeted approach for P-gp inhibitors via nasal delivery therefore was explored. The nasal route conferred compound-specific brain exposure advantages among three model inhibitors. However, the ability of this route to deliver a mass of drug required to confer the desired pharmacologic effect was insufficient; the profound inhibition of BBB P-gp needed for meaningful increases in brain exposure after systemic administration of paclitaxel could not be achieved. A fundamental limitation of the model system was slow paclitaxel equilibration between blood and brain. Mathematical simulations explored relationships between accuracy of assessment of brain partitioning, including the influence of P-gp on partitioning, and sampling time. These simulations identified a previously undescribed effect of peripheral distribution on the kinetics of brain partitioning. Using data-mining and targeted prospective experimentation, distribution into a peripheral pharmacokinetic compartment was identified as a novel mechanistic explanation for previously unexplained time-dependent decreases, rather than increases, in brain partitioning of the antiepileptic, valproate. Taken together, these studies identify an important cause of erroneous assessment of P-gp impact on brain exposure, elucidate fundamental kinetic processes underlying the distribution of drugs into brain, and establish a framework for metrics that can provide appropriate descriptions of CNS exposure.