In Vitro characterization of narciclasine: solubility, metabolic stability, and P-glycoprotein substrate status
Abstract
Background Narciclasine has demonstrated anticancer activity at low nanomolar concentrations in various preclinical cancer models, but no clinical data in cancer patients are available. Although its biological activity and structure-activity relationships are relatively well characterized, the pharmacological properties of narciclasine have not been reported. This information will benefit the research to further develop narciclasine. The goal of the current study is to characterize the physicochemical properties, metabolic stability, and P-glycoprotein substrate status of narciclasine. Methods We first developed a robust HPLC-tandem mass spectrometry assay to measure narciclasine in mouse plasma. Then, we assessed the stability, metabolic pathways, and cytochrome P450 inhibitory effect of narciclasine. We also evaluated narciclasine for its P-glycoprotein substrate status using two methods: 1) Caco-2 permeability assay, and 2) cytotoxicity assay in human cancer cells with exogenous expression of P-glycoprotein. Results Narciclasine was stable in the plasma of the four species tested. It showed metabolic stability in human liver microsomes and hepatocytes, but in other species, metabolic clearance was higher than in humans, indicating that humans may metabolize narciclasine minimally. Further studies to identify the metabolic pathway of narciclasine detected trace amounts of reduction and glucuronidation in human liver microsomes. Narciclasine was highly soluble under both…
Read the paper
Related studies
- Challenges and opportunities with drug repurposing: finding strategies to find alternative uses of therapeutics
- Challenges in Chagas Disease Drug Development
- T Cell Specificity: A Great Challenge in Chagas Disease
- Benznidazole treatment leads to DNA damage in Trypanosoma cruzi and the persistence of rare widely dispersed non-replicative amastigotes in mice
- Rapid Molecular Detection of Terbinafine-resistant Dermatophytes
- Identifying novel drugs with new modes of action for neglected tropical fungal skin diseases (fungal skinNTDs) using an Open Source Drug discovery approach
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.