Abstract

Drug Metabolism, Brain Permeation and Transport in the Desert Locust Schistocerca gregaria

PhD Thesis abstract by Olivia Dzwonkowski, Department of Pharmacy, University of Copenhagen

Drug discovery today is a highly regulated area within the pharmaceutical industry, endeavouring to develop safe candidates for clinical studies. Researchers in the industrial and academic environment, are facing a growing ethical and commercial pressure to move from testing drug candidates in live animals. Also, they are confronted with a lack of appropriate test systems to assess central nervous system-specific parameters of drug candidates, as well as reference standards of relevant drug metabolites. Novel testing platforms emerge to compensate for these restrictions by offering the evaluation of relevant parameters that are vital for the drug discovery process.

In this work, the desert locust served to evaluate its accessibility and suitability for in vitro, in vivo, and ex vivo testing platforms. Preparations of locust microsomes served to explore potential for metabolite synthesis. Liquid chromatography, coupled to high-resolution mass spectrometry, enabled the tentative identification of relevant metabolites known from human. The attempt to generate and collect morphine metabolites in vivo resulted in an innovative technique for exhaustive hemolymph collection. The analysis of metabolites revealed analogies to mammalian morphine metabolism.

The existing ex vivo locust brain model was employed to assess brain permeation and transport of morphine and cannabidiol. Inconsistencies within the findings led to the development of an innovative estimation method for locust brain sizes via microscopy. The results for morphine permeation revealed that further optimization would be required to assess reliable compound permeability data.

The desert locust insect model offers diverse application platforms anticipating inter- esting information that could contribute to progress future drug candidates further in the discovery process.