Physicochemical assays, pharmacokinetics, and tissue distribution of ARN14988, an acid ceramidase inhibitor, for glioblastoma therapy.

in International journal of pharmaceutics by Vilashini Rajaratnam, Mohammad Mohiminul Islam, Ethan F Kub, Franca Ohikhuare, Shama P Mirza

TLDR

  • The study evaluated the physicochemical properties and pharmacokinetics of ARN14988, an acid ceramidase inhibitor, and found that it has potential as a glioblastoma treatment due to its ability to cross the blood-brain barrier.
  • The study provides preclinical evidence for the use of ARN14988 in glioblastoma treatment and highlights the need for further research into its formulation and delivery.

Abstract

ARN14988, an acid ceramidase inhibitor, has shown cytotoxicity towards glioblastoma in our previous studies. In this study, we investigated the physicochemical parameters, pharmacokinetics and biodistribution of ARN14988. The physicochemical evaluation of ARN14988 was carried out in vitro using shake-flask lipophilicity assay, parallel artificial membrane permeability assay (PAMPA), and rapid equilibrium dialysis (RED) plasma protein binding assay. The lipophilicity of ARN14988 is determined to be log K= 3.34 ± 0.40 indicating that ARN14988 can potentially accumulate in lipid compartment. The apparent permeability of ARN14988 is high, log P = -4.62 ± 0.18, at biological pH, suggesting ARN14988 can cross the blood-brain barrier and potentially be used for the treatment of brain cancer. The plasma protein binding assay found that about 45 % of ARN14988 remains unbound to plasma protein. Pharmacokinetics and biodistribution of ARN14988 in vivo were studied in mouse model via intraperitoneal injection. ARN14988 was found to be rapidly distributed into liver and kidney. The peak concentration of ARN14988 in brain was 17.36 ± 1.44 ng/mL suggesting that it could cross the blood-brain barrier. To our knowledge, this is the first report on preclinical evaluation of ARN14988 via intraperitoneal injection in mice, and it provides information for future development of ARN14988 as glioblastoma drug candidate.

Overview

  • The study aimed to evaluate the physicochemical parameters, pharmacokinetics, and biodistribution of ARN14988, an acid ceramidase inhibitor, to investigate its potential as a glioblastoma treatment.
  • The physicochemical properties of ARN14988 were assessed using shake-flask lipophilicity assay, parallel artificial membrane permeability assay (PAMPA), and rapid equilibrium dialysis (RED) plasma protein binding assay.
  • The study was conducted in vitro and in vivo using mouse model via intraperitoneal injection to determine ARN14988's accumulation, permeability, and biodistribution.

Comparative Analysis & Findings

  • The results showed that ARN14988 has a log K value of 3.34 ± 0.40 indicating its potential to accumulate in lipid compartments.
  • The apparent permeability of ARN14988 was found to be high, log P = -4.62 ± 0.18, suggesting that it can cross the blood-brain barrier.
  • The plasma protein binding assay found that approximately 45% of ARN14988 remains unbound to plasma protein.

Implications and Future Directions

  • The study provides preclinical evidence for the potential use of ARN14988 as a glioblastoma treatment, highlighting its ability to cross the blood-brain barrier.
  • Future studies should focus on optimizing the formulation and delivery method of ARN14988 to maximize its therapeutic potential.
  • The results also suggest the need for further investigation into the pharmacokinetic and biodistribution profiles of ARN14988 in larger animal models and clinical trials.
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