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Toxicologie.nl

Symposium 7 Symposium on Transporters and Relevance to Exposure Levels
Chairs: Professor Gabrielle Hawksworth, University of Aberdeen and
Professor Frans Russel, (Radboud University Nijmegen, The Netherlands)
The first speaker of the symposia was Professor Frans G.M. Russel (Radboud University Nijmegen
Medical Centre, The Netherlands). Professor Russel started his talk by explaining the role and
importance of transporters in toxicity studies. Both uptake and efflux transporters were discussed and
their coordinated function with drug metabolising enzymes was explained as an important aspect of
physiological systems. Professor Russel further explained the role of ABC transporter in determining
xenobiotic accumulation and toxicity in various organs with special reference to the renal toxicity. The
talk was concluded with the remarks that uptake and efflux transporters are important players in
determining xenobiotic disposition, exposure and toxicity.
Second speaker of the symposia was Dr Jashvant Unadkat (University of Washington, Seattle, USA)
who talked about the role of transporters in drug efficacy, toxicity, and mitochondrial exposure. He
started his talk by introducing transport systems in sub-cellular organelles and their role in drug
efficacy and toxicity with special emphasis on mitochondria. He explained how the presence and
absence of these membrane transporters in mitochondria can determine the level of exposure,
efficacy, and toxicity of a specific drug. Nucleoside drugs, filauridine, gemcitabine, and ribavirin were
discussed as specific examples by looking at their transport across the mitochondrial membrane and
the mechanism of toxicity. Interspecies species difference was highlighted in the case of filauridine, a
lethal mitochondrial toxin in humans but does not have any effect on rodents even on 1000 fold
increased dose as ENT1 transporter on mitochondrial membrane, responsible for uptake of this drug,
is not present in rodents. Dr Unadkat concluded his talk with the emphasis on important role of
mitochondrial transport systems in drug toxicity and the need to include these studies in drug
development to avoid the adverse effects at later stages.
Third talk of the symposia was delivered by Dr Alfred H. Schinkel (Netherlands Cancer Institute, The
Netherlands). Dr Schinkel’s area of interest is in vivo knockout models of transporters to study
xenobiotic exposure. He started his talk by giving a brief background of their research and interest in
these models which was studying the knock out effects of transporter proteins responsible for drug
resistance in tumours. He showed the data that knocking out efflux transporters such as p-gp and
Bcrp1 they observed a huge difference in oral availability of various drugs. They also studied the
pharmacological and physiological functional overlap between drug resistance proteins. Dr Schinkel
also explained the adverse effects in terms of higher levels of toxicity, especially hepatotoxicity and
nephrotoxicity resulting from knocking down these transporters in vivo. Finally he discussed that how
they are using this data for modelling biological system in order to predict drug, disposition efficacy,
and toxicity in various organs.
Final speaker of the symposia was Professor Amin Rostami-Hodjegan (University of Manchester and
Simcyp Limited, Sheffield, UK) who discussed the exposure modelling and simulation with transporter
data. Professor Rostami-Hodjegan explained the existing models of exposure, their inclusion criteria
and limitations. He detailed exposure models used for toxicology and pharmacology with various good
examples. Inclusion of transporters in these models was discussed in terms of criteria such as
transport effects and how effective can be in the given model. The talk was concluded with the
remarks that modelling is a dynamic, multilevel, and ever evolving phenomenon that needs continuous
feeding in of new data to make it more productive.
Symposium Report by Mohammad Farooq

Source: http://www.toxicologie.nl/userfiles/File/Symposium%207%20Exposure.pdf

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