Physicochemical Properties, Pharmacokinetics and Biodistribution of ARM14988, an Acid Ceramidase Inhibitor, and Its Potential as Chemotherapeutic Agent for Glioblastoma

Abstract

Glioblastoma (GBM) is one of the most common and detrimental forms of brain tumor. While there are few FDA-approved chemotherapeutic treatments, the overall survival is still poor leading to many studies dedicated to developing more effective treatment options. Previous studies have identified acid ceramidase (ASAH1) as a potential therapeutic target for this disease. ARN14988, an ASAH1 inhibitor, has shown to be highly cytotoxic compared to the FDA-approved chemotherapy agent, temozolomide, in GBM cell lines. This initial finding makes ARN14988 a desired candidate for further drug discovery studies. Herein, the objective of this thesis is to study the pharmacological properties of ARN 14988 as a potential chemotherapeutic agent for GBM. The first part of this thesis focuses on understanding the physicochemical properties of ARN14988 by utilizing in vitro assays to measure the lipophilicity, blood-brain barrier permeability, and protein plasma binding activity. The results indicated that ARN14988 is lipophilic with about 45% remaining unbound in plasma that can cross blood-brain barrier. The second part concentrates on developing and validating a liquid-chromatography mass spectrometry (LC-MS/MS) method for the quantification of ARN14988 in rodent plasma and tissues. The developed method was sensitive, selective, precise, and accurate with a linear range of 10 ng/mL to 5000 ng/mL. Furthermore, this method demonstrated good extraction efficiencies with minimal matrix interference. The third part of this thesis centers on understanding the pharmacokinetics and drug distribution of ARN14988 in a mouse model using the validated LC-MS/MS method. After the drug administration, the plasma pharmacokinetic parameters of ARN14988 exhibited rapid absorption and elimination in mouse. ARN14988 was also found to be extensively distributed in kidney, liver, and brain tissues. The final part of this thesis focuses on the spatial biodistribution of ARN14988 in mouse brains using imaging mass spectrometry (IMS). Parallel to the LC-MS/MS analysis, the IMS analysis visualized the deposition of ARN14988 throughout the brain tissues. This in vivo study showed that ARN14988 can cross the blood brain barrier to reach the targeted tissue, brain, for GBM.