We have an open position for a PhD candidate at the Department of Pharmacy, Uppsala University (http://www.farmfak.uu.se/farm/index_en.shtml). This project is part of the EU-funded project ARIADME: Analytical Research in ADME profiling (http://pharm.kuleuven.be/pharbio/ariadme). ARIADME is a Marie Curie project which involves 4 academic centers and 10 industrial partners. The PhD candidate will be enrolled in the UU doctoral school program and is expected to contribute to network wide training events of the ARIADME project. The project will be performed in professor Per Artursson's research group in collaboration with Roche, Basel, Switzerland.

Objectives:

Since intracellular unbound drug exposure drives all pharmacokinetic, pharmacological and toxicological processes inside human cells, an unmet need exists for methods to determine and predict this parameter. The current lack of relevant information on local exposure may result in misleading predictions of intracellular drug effects. In this project, the aim is to develop innovative experimental and computational ADME models that enable rapid and accurate determination of intracellular drug exposure, with specific emphasis on how transporters affect unbound drug concentrations and metabolism. Global and targeted proteomics of isolated human hepatocytes and of highly defined transporter cell models will be used to accurately determine and scale the impact of different transport processes. Recently, a novel visually-guided and intuitive mechanistic modeling approach to quantify the impact of transporters on intestinal drug absorption was developed. In this project, this model will be expanded to drug distribution and turnover, specifically in the human liver. This approach, which is readily adaptable to other tissues, will allow exploration of how variability arising from genetic differences or drug-drug interactions affects drug disposition in the liver. During the secondment period at Roche, the model will be validated against in-house compounds with known in vivo performance, and incorporated in physiologically based pharmacokinetic (PBPK) models. Unparalleled prediction is expected from the integration of unique components in the model: 1) exact determination of intracellular unbound drug concentrations using sensitive ultra-performance LC-MS/MS analytics and 2) state of the art proteomics-informed scaling of transporter impact from highly defined cell models to human tissue in vivo. The overall aim of this research project is:

• To develop innovative experimental and computational ADME models that enable rapid and accurate determination of intracellular drug exposure.

Main Tasks:

• To develop innovative experimental methods for rapid and accurate determination of intracellular drug exposure in in vitro systems
• To apply those novel methods to assess the impact of drug transporters on intracellular drug exposure and metabolism
• To link the results of in vitro experiments to the in vivo situation by using results from proteomics and computational ADME models
• To explore how inter-individual variability arising from genetic differences affects drug disposition and exposure.

Formal requirements:

The highly motivated candidate should hold an MSc degree in relevant field.

Applications should be made via the Uppsala University job portal via the Apply button below.

Questions and enquiries should be sent to Prof. Per Artursson, e-mail: per.artursson@farmaci.uu.se

The candidate should have less than 4 years' of research experience and must not have resided or carried out his/her main activity in Sweden for more than 12 months during the 3 years immediately prior to the recruitment. This is due to an EU funding stipulation.

Closing date: November 8th 2013. 

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