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Title: Expression, regulation and substrate specificity of organic cation transporters in human renal cell systems
Author: Duffy, Kevin
ISNI:       0000 0001 3434 1282
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2006
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Active uptake of the organic cation, tetraethylammonium (TEA), was shown in freshly isolated human and rat PT cells. This uptake was both inhibitable and temperature dependent. Several other drug substrates including ipratropium, procainamide, amantadine and pindolol were also actively taken up by fresh HPT cells. The human organic cation transporter, hOCT2, is the principal uptake transporter in the human proximal tubule. HEK cells transfected with hOCT2 were used to screen several drugs as possible substrates for this transporter. Substrates identified included TEA, amantadine, quinine, quinidine, procainamide, pindolol, oxytropium, ipratropium, and imipramine. Kinetic parameters for five of these were used to calculate their intrinsic clearances, which were correlated with renal clearance values in vivo. This correlation was significant (R2=0.814), suggesting that the HEK-hOCT2 cell line can be used to make predictions of the renal clearance expected in man for compounds that are hOCT2 substrates. The second-messenger pathways involved in the regulation of organic cation transport in freshly isolated HPT and RPT cells and HEK-hOCT2 cells were elucidated. Several pathways, most notably involving ALP, PKC and calmodulin, are involved in the regulation of organic cation transport in all these systems. Quantitative RT-PCR and immunoblotting were used to detect changes in expression of organic ion transporters in primary cultures of PT cells compared with those in vivo. Expression of apical ion transporters was maintained in these culture systems, while expression of those located basolaterally was down-regulated. As well as successfully predicting in vivo clearance data from cellular uptake rates in vitro, this is the first comprehensive study correlating functional organic cation transport mechanisms with a number of signalling pathways in human renal proximal tubules.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available