Spatial expression and functionality of drug transporters in the intact lung: objectives for further research.
This commentary provides a background appraising evidence in the intact lung on the spatial expression of drug transporters and, where available, evidence in the intact lung of the impact, or otherwise, that such transporters can have upon pulmonary drug absorption and disposition. Ultimately drug discovery and development scientists will wish to identify in a 'pulmonary' context the effect of disease upon transporter function, the potential for drug transporters to contribute to drug-drug interactions and to inter-individual variation in drug handling and response. The rate and extent of lung epithelial permeation of drugs involve an interplay between the dose and the deposition site of drug within the lung and physiological variables operational at the epithelial-luminal interface. Amongst the latter variables is the potential impact of active transporter processes which may well display regio-selective characteristics along the epithelial tract. In pulmonary tissues the spatial pattern of drug transporter expression is generally poorly defined and the functional significance of transporters within the intact lung is explored in only a limited manner. Active transporters in the lung epithelium may affect airway residence times of drug, modulate access of drug to intracellular targets and to submucosal lung tissue, and potentially influence airway to systemic drug absorption profiles. Transporters in the lung tissue may also have the capacity to mediate uptake of drug from the systemic circulation resulting in drug accumulation in the lung. Transporters have physiological roles and new drug candidates while not necessarily serving as transport substrates may modulate transporter activity and hence physiology. The commentary highlights a series of recommendations for further work in pulmonary drug transporter research.
Gumbleton
Mark
M
Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF103NB, United Kingdom. gumbleton@cardiff.ac.uk
Al-Jayyoussi
Ghaith
G
Crandon-Lewis
Adam
A
Francombe
Danielle
D
Kreitmeyr
Katharina
K
Morris
Chris J
CJ
Smith
Mathew W
MW
D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism*; D055808:Drug Discovery / Q000379:methods; D004347:Drug Interactions; D006801:Humans; D007206:Individuality; D008168:Lung / Q000378:metabolism*; D010599:Pharmacokinetics
D002352:Carrier Proteins