Carsten Uhd Nielsen
Lektor
E-mail: cun(at)farma.ku.dk
Telefon: 35 33 64 72
Rum: 13/423a

Intestinal drug delivery via hPAT1.
The aim of this project is to understand the role of transporters in defining the oral absorption of hPAT1 substrates such as gaboxadol, vigabatrin and delta-aminolevulinic acid. The scientific questions relate to how large a fraction of intestinal drug absorption is carrier-mediated vs. passive, how is the absorption affected by food components and other drug substances, i.e. drug-food and drug-drug interactions, are other transporters involved in the intestinal absorption. There are in other words broad possibilities for setting up a project depending on the interests of the master student. Methods involve cell culture experiments (perhaps external in vivo studies), transport kinetics and analytical assays.
Supervisor: Carsten Uhd Nielsen
Max. nr. of students: 4

The role of hPAT2 in renal drug absorption
This project aim at investigating if PAT2 recognized similar substrates as PAT1, and if dipeptides are substrates of PAT2, similarly to what has been observed for PAT1. This may help in defining a role of PAT2 in re-absorption of drug substances from the renal tubules. The project is basic research as a model system (cell based or in oocytes) has to be developed in order to study PAT2.
Supervisor: Carsten Uhd Nielsen
Max. nr. of students: 1-2

Identification of a high affinity inhibitor of hPAT1
Currently, the best inhibitor (5-hydroxy-trypthophan) for PAT1 has a moderate affinity and is moreover toxic when used in in vivo animal studies. This makes it difficult to investigate the impact of PAT1 in drug transport both in vitro and in vivo. There is thus a need for an identification of specific inhibitors with high affinity. The structural requirement for targeting amino acid analogs and selected drug substances to hPAT1 is investigated in the present project. The project therefore aims at elucidating structural determinants which are important for transport via hPAT1. The methods involved are uptake studies in cell cultures and/or oocytes as well as creative ligand-based drug searching.
Supervisor: Carsten Uhd Nielsen
Max. nr. of students: 2

Mechanism-based investigations of transporter-mediated drug-drug interaction
A number of drug substances have recently been identified as non-competitive inhibitor of amino acid (PAT1) and peptide (PEPT1) transporters. The mechanism behind these interactions is poorly understood. This project therefor aims at investigating the underlying reasons for the observed functional effects of drug substances on PAT1 and PEPT1. Are the effects observed directly coupled to transporter binding or is it a result of pharmacologic or toxicological effects on epithelial cells mediating reduced transporter-mediated transport as a secondary response? Investigations are mainly based on cell culture methods with uptake studies, measurements of membrane potential and calcium release.
Supervisor: Carsten Uhd Nielsen
Maximal number of students: 1-2

In vitro characterisation of gaboxadol absorption
The proton-coupled amino acid transporter, PAT1, has been shown to be important for the absorption and thereby the delivery of some amino acid mimetic drugs. Recently the in vivo absorption of the GABA-analogue gaboxadol was shown to be dependent on PAT1 function. One essential step in the oral absorption of gaboxadol seems to be the translocation via PAT1 into the epithelial cells however; this needs to be characterized further. Moreover, the basolateral transport mechanism (transport from the epithelial cells to the blood) is still unknown. The aim of the project is therefore to characterise the apical and basolateral transport of gaboxadol in cell cultures. This project can be modified on the choice of substrate, the type of cell culture and the analytical method.
Supervisor: Mie Larsen Broberg/Carsten Uhd Nielsen
Max. nr. of students: 1-2