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Start of funding 01.07.2013
Role of drug transporters in the pulmonary absorption of inhaled drugs
Prof. Dr. Petra Högger
University of Würzburg
Prof. Dr. Kathleen M. Giacomini
University of California, San Francisco
Department of Bioengineering and Therapeutic Sciences
Drug transporters play a major role in pharmacokinetics, e.g. in drug absorption, elimination or accumulation in tissues. Although it is known that various drug transporters are present in the human lung, the influence of transporter expression in vivo on the pharmacokinetics of inhaled drugs and potential consequences for drug therapy are not been well understood yet.
In a joint project, junior researchers of the group of Prof. Giacomini (University of California, San Francisco) and Prof. Högger (University of Würzburg) will characterize the rate and extent of the pulmonary absorption of a drug transporter substrate employing a human lung reperfusion model. Tissue samples of the respective lungs will be subjected to an analysis of gene and protein expression of pulmonary drug transporters so that the individual expression profiles can be paralleled with the pharmacokinetic behavior of the inhaled drug.
Final report:
Within the scope of this joint project the influence of drug transporters in human lung tissues on the pulmonary absorption of inhaled drugs was examined. Therefore we investigated the mRNA-expression levels of drug transporters in 75 human lung tissue samples by qPCR technique. First results indicated that among various drug transporters the organic cation transporter 3 (OCT3) was most abundant whereas OCT2 could hardly be detected.
Besides, we investigated the pharmacokinetic properties of the anticholinergic ipratropium bromide (IB) using the ex-vivo human isolated perfusion lung model that is well-established at the university of Würzburg. No inhibitory effect on pulmonary absorption was observed with prior administration of l-carnitine, an inhibitor of the organic cation / carnitine transporter 1 and 2 (OCTN1/2). These results suggested that IB was mainly transported by OCT1 and / or OCT3.
During a second research stay we wanted to investigate and verify this hypothesis by conducting uptake studies with tritium-labeled IB in stably transfected HEK293 cells (HEK-h-OCT1 and HEK-h-OCT3). A contribution of both OCT1 and OCT3 to the cellular uptake of [3H]-IB could be confirmed.
The results of the joint project between the groups of Prof. Giacomini (University of California, San Francisco) and Prof. Högger (Universität Würzburg) generate a better understanding of the absorption processes in human lung tissues. Furthermore, the complementary methods used in both labs provide the opportunity to investigate the competition of active compounds and potential interactions in-vitro as well as ex-vivo.