Metabolism and CNS Distribution of Selected Histone Deacetylase Inhibitors

Abstract

Brain tumors are the leading cause of cancer-related death in children and efficacious treatment remains a critical unmet need. The blood-brain barrier (BBB) is a major hurdle for effective delivery of treatments for tumors in the central nervous system (CNS). While the paracellular transport of large, hydrophilic molecules is largely limited by tight junctions, efflux transporter systems are a key element of the BBB that can limit the penetration of lipophilic drugs. Histone deacetylase inhibitors (HDACIs) have been widely explored for their application in oncology, including the field of neuro-oncology. Despite their high in vitro potency and CNS-penetration-favorable physicochemical properties, the in vivo efficacy of HDACIs has been poor for CNS tumor treatment. This lack of in vitro-in vivo correlation may be in part attributed to poor CNS distribution. In this thesis project, we investigated the CNS distribution of three potent HDACIs, panobinostat, vorinostat, and quisinostat, following systemic administration. We characterized the systemic pharmacokinetics and CNS distributional kinetics of these compounds in wild-type and transgenic mice lacking p-glycoprotein (P-gp) and/or breast cancer resistance protein (Bcrp), two major efflux transporters expressed at the BBB. The in vitro stability studies show that all three hydroxamic acid-based HDACIs are enzymatically metabolized in mouse plasma, highlighting the need for careful sample handling to have accurate measurements of in vivo drug concentrations. In vivo experiments in the different mouse genotypes show that the CNS distribution of panobinostat and quisinostat is moderately limited by P-gp, but not Bcrp. Although the CNS penetration of vorinostat was not restricted by P-gp and Bcrp, its small unbound CNS tissue-to-plasma partition coefficients suggest that other efflux transporters could be involved. In addition, our results show that a tolerable dosing regimen of panobinostat would not result in adequate CNS exposure of unbound panobinostat in patients. In summary, our data show that the lack of adequate exposure of the active moieties can be a major reason for the lack of efficacy of these HDACIs in the CNS when systemically delivered. This result indicates that alternative approaches to improve delivery (e.g., convection-enhanced delivery or focused ultrasound) should be considered.