P-glycoprotein (P-gp – MDR-1), a 170 kDa glycosylated membrane bound protein, is a member of the ATP-binding cassette transporter family. The potential for P-gp to reduce drug absorption across lung epithelia is of significant interest; this is particularly so, given P-gp’s broad substrate specificity mediating efflux transport of a range of structurally unrelated substrates. Within lung, Pgp expression is evident in bronchial and alveolar epithelia with functional characterisation of P-gp transport capacity within lung epithelial cells currently restricted to respective in-vitro cell culture models. The aims of this project were to establish the relative mRNA expression of several ATP Binding Cassette (ABC), Solute Carrier (SLC) and Solute Carrier Organic Anion (SLCO) drug transporters within rat lung samples through use of RT-PCR; expression suggesting the potential to serve as targets for pulmonary drug delivery. Further, validation of an Isolated Perfused Rat Lung preparation for use in assessment of drug transport across the lung was conducted. In order to assess the functional significance of the ABC drug transporter, P-glycoprotein, on drugs instilled intra-tracheally to the IPRL set-up, use of the P-gp substrates; Rhodamine 123 (Rh123), digoxin, and flunisolide and the P-gp inhibitor, GF120918 was employed. Further, use of kinetic modelling was employed to establish pharmacokinetic parameters involved. Using the IPRL, the P-gp dependent pulmonary absorption of the P-gp substrate, Rh123, was demonstrated. Dose-dependent absorption, consistent with a saturable component in the molecule’s pulmonary absorption, was demonstrated. Further, the absorption of low dose Rh123 was promoted by the presence of the highly selective P-gp inhibitor GF120918, consistent with a functional role of P-gp mediated efflux within an intact lung; an efflux process which may limit the pulmonary absorption of a lung administered molecule. Further studies using this system and extending the range of molecules studied will provide greater understanding of the quantitative significance of P-gp in limiting pulmonary absorption across lung epithelium.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:567166 |
| Date | January 2011 |
| Creators | Francombe, Danielle |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/15330/ |
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