Diploma Work 30 hp - Planned for spring 2014

Optimization study for trapping reactive metabolites



Your role:

Find optimal conditions for quenching a microsome incubation that is used for trapping reactive metabolites with GSH.



The project will be at the department of Drug Metabolism and Pharmacokinetic (DMPK). DMPK support drug projects with experimental results and knowledge from in vitro experiment. An essential task is to identify reactive metabolites formed from the drug compound as early as possible in the drug project. Reactive metabolites may bind with macromolecules and cause toxic effects in vivo. A number of methods are used for identifying reactive metabolites where one is Glutathione (GSH) trapping. In the GSH trapping method drug compound is incubated with human liver microsomes together with GSH. Reactive metabolites that are formed during the incubation can react with GSH and forms a stable adduct that can be identified by LC-MS.



Microsomal incubation with drug compound is a well established method for measuring clearence of drug compounds in vitro. However the method is developed for measuring clearence of drug compounds and not the formed metabolites. For example, it has been shown that higher concentrations of GSH-adducts are found closer to the percipitate then in the supernate that is analyzed for metabolite identifications. Evaluation of type of organic solvent that is used for quenching the reaction and the volume of solvent are parameters that will be evaluated in this project.



Experimental design will be used for optimizing the parameters in the microsome incubation and Modde will be used as tool. In order to have control over the parameters the incubations will be done on a robot. Samples will be analyzed on a UPLC-QTOF instrument in order to detect the amount of unknown GSH-adducts.



Your experience:

Analytical chemist, Pharmaceutical chemist or Pharmacist



Business: AstraZeneca



City: Mölndal



Deadline for applications: 2013-12-06



More information:. Sara Amberntsson, 031 - 7761000, Sara.Amberntsson@astrazeneca.com



Work at AstraZeneca:

AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialization of prescription medicines for some of the world's most serious diseases. But we're more than one of the world's leading pharmaceutical companies. At AstraZeneca, we're proud to have a unique workplace culture that inspires innovation and collaboration. Here, employees are empowered to express diverse perspectives - and are made to feel valued, energized and rewarded for their ideas and creativity.