Investigation of lysosomal trapping of drugs and implications on the assessment of intracellular drug concentration 

Dr Aleksandra Galetin and Dr David Hallifax

Intracellular concentration of a drug is an important determinant of its efficacy, toxicity, and potential drug-drug interactions. In the case of lipophilic compounds, electrochemical and pH gradients across the plasma and organelle membrane can lead to preferential subcellular distribution of drugs based on their charge and/or ionization potential. For example, cationic amphiphilic drugs have been reported to sequester in lysosomes in organs such as liver and lungs.

This accumulation is pH-driven, as the more acidic pH in lysosomes facilitates ionization of basic drugs, ‘trapping’ them within organelle due to reduced ability of the protonated form to diffuse back into the cytosol. Lysosomal trapping can result in significantly higher lysosomal drug concentration in comparison to the cytosol and this may have an important therapeutic consequence for many clinically used basic drugs. In certain instances, lysosomal accumulation is the prerequisite for therapeutic efficacy (e.g., antimalarial drugs), whereas accumulation of some drugs in alveolar macrophages may lead to phospholipidosis.

The aim of this project is to investigate potential lysosomal sequestration of a range of drugs with differential physicochemical properties. Lysosomal accumulation of selected drugs will be assessed in either hepatocytes or alveolar macrophages as cellular models using a range of methods. Data generated will be used for the refinement of the currently developed in house in silico cell model for the prediction of intracellular drug concentration and likelihood of lysosomal accumulation.

The project will allow the successful candidate to develop a number of research and technical skills in regards to different in vitro cellular systems and modelling of cellular distribution based on the physicochemical properties and cell composition. Successful completion of this PhD would be an ideal platform for progression into a variety of career positions within academic or industrial settings involving biotechnology, modelling and simulation.

Applicants should hold (or expect to obtain) a minimum upper-second honours degree (or equivalent) in pharmacology, biochemistry, or a related chemistry/biological science area. A strong mathematical background is essential. Previous experience of in vitro systems (e.g., hepatocytes) or cell culturing and mathematical modelling would be an advantage.

This 4-year full-time studentship provides full support for tuition fees and annual minimum tax-free stipend of £15,500. The project is due to commence in October 2013 and is open to UK/EU nationals only due to the nature of the funding.

Please direct applications in the following format to Dr Aleksandra Galetin (aleksandra.galetin@manchester.ac.uk):

• Academic CV
• Official academic transcripts
• Contact details for two suitable referees
• A personal statement (750 words maximum) outlining your suitability for the study, what you hope to achieve from the PhD and your research experience to date.

Any enquiries relating to the project and/or suitability should be directed to Dr Galetin. Deadline for applications: Monday 12 August 2013.

http://www.pharmacy.manchester.ac.uk/staff/agaletin/

http://www.pharmacy.manchester.ac.uk/capkr 

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