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How does cross-talk between drug transporters and drug metabolism affect drug disposition

Objective

The availability of in vitro models that mimic Absorption, Distribution, Metabolism, and Excretion (ADME) of new drugs in human combined with a thorough mechanistic knowledge about the processes that determine ADME, would greatly benefit the development of novel medicines. In many cases the hepatic uptake of drugs is mediated by Organic Anion Uptake Transporters (OATPs). Intracellularly, drugs are metabolized in two steps, termed phase I and phase II of drug metabolism which are catalysed by enzymes such as cytochromes P450 andUDP glucuronosyl- or suIfo-transferases respectively. The resulting conjugates are eliminated into the bile by drug efflux pumps.It is our objective to investigate the interaction of these various systems in vitro in recombinant cell l ines. The systems to be studied include human drug metabolizing enzymes (eg. sulfo-transferases and UDP-glucuronosyltransferases) and drug carriers (eg. Organic Anion Uptake Transporters (OATPs) and Multidrug Resistance Related Protein (MRP) efflux pumps). The project would be realized through a partnership between the Development Centre of Eli Lilly in Belgium and the University of Dundee. An experienced researcher would be hired by Lilly and would work for two years at Dundee where he would apply genomics for the characterization of cell line enzymes and molecular biology for the expression of human enzymes and carriers in those cell lines. During this period he would also spend some time at Lilly for the validation of the systems using specific probe subs trates. The researcher would benefit from the knowledge in genomics, proteomics, cell biology at Dundee and would transfer this knowledge at Lilly where he/she would return after two years, to implement therethese in vitro systems to screen new drugs and b etter predict their ADME characteristics. Researchers from Dundee would benefit from the experience of Lilly in analytical techniques used in ADME (e.g. mass spectrometry).

Call for proposal

FP6-2002-MOBILITY-3
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Funding Scheme

TOK - Marie Curie actions-Transfer of Knowledge

Coordinator

LILLY DEVELOPMENT CENTRE SA
Address
Rue Grandonpre, 11
Mont Saint Guilbert
Belgium

Participants (1)

UNIVERSITY OF DUNDEE
United Kingdom
Address
Nethergate
Dundee