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Examining the selectivity in the impact of pulmonary P-gp upon the absorption of its substrates using an IPML model with knockout mice

Price, Daniel F. 2015. Examining the selectivity in the impact of pulmonary P-gp upon the absorption of its substrates using an IPML model with knockout mice. PhD Thesis, Cardiff University.
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Abstract

P-glycoprotein is an ATPase binding cassette (ABC) drug-transporter protein represented by MDR1 in humans and mdr1a and mdr1b in mice. The substrate specificity of this protein is unusually large due to the polyspecific nature of its binding pocket and as a result a wide range of endogenous and exogenous compounds are effluxed by this transporter. There is a large body of literature about the role of P-glycoprotein in limiting the absorption of drug substrates at a number of barriers but currently data in the lung is limited. P-gp expression and localisation studies have confirmed its presence in lung tissue but there is conflicting data with regards to the functional relevance on lung absorption. The aims of this project were to establish a knockout, mdr1a/b (-/-), isolated perfused mouse lung model (IPML) to investigate the role of pulmonary P-gp upon lung delivery. Utilising the lungs of knockout mice in the IPML allowed the investigation of P-gp function with the effects of chemical inhibition which may have resulted in the discordance observed in its functional significance in the literature. IPML experiments were conducted with a panel of 18 P-gp substrates which were chosen for diversity in their physicochemical characteristics. The discordance in P-gp functionality in the lung observed in the literature was replicated in the IPML model. Ten of the substrates showed significant efflux from the lung by pulmonary P-gp whereas the absorption of the remaining eight was unaffected. Further studies into the mechanism behind the differential effects of pulmonary P-gp showed that it was a barrier specific effect as it was not observed in the intestine. The effect was also not explained by differences in the P-gp binding kinetics off the substrates. Investigations in to the membrane affinity of the panel revealed a potential mechanism for the selectivity of P-gp in the lung with regards to the passive permeability of the molecules and specifically the paracellular pathway.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: Pulmonary; P-gp; IPML Model
Date of First Compliant Deposit: 30 March 2016
Last Modified: 15 Oct 2016 04:36
URI: http://orca-mwe.cf.ac.uk/id/eprint/84217

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