Elsevier

Advanced Drug Delivery Reviews

Volume 63, Issues 1–2, January–February 2011, Pages 110-118
Advanced Drug Delivery Reviews

Spatial expression and functionality of drug transporters in the intact lung: Objectives for further research

https://doi.org/10.1016/j.addr.2010.09.008Get rights and content

Abstract

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.

Section snippets

Perspective

The role of carrier transporters in the absorption and disposition of low-molecular weight drugs and solutes has been the subject of intense study at intestinal, hepatic, renal and blood-brain barriers. Active transport processes for drugs are implicated in altering drug concentrations at the target receptor, in drug–drug interactions and can be subject to functional modulation by disease. Beyond the impact upon drug absorption and disposition per se, a drug substrate may also modulate

P-glycoprotein

P-gp belongs to the ABC subfamily B (gene name ABCB1) and is a widely studied efflux transporter with substrates comprising a broad array of structurally diverse molecules across a range of therapeutic classes. Structure–activity relationships [3], [4], [5] indicate P-gp substrates to be lipophilic or display amphiphilic properties that afford access of the substrate to P-gp binding sites from within the plasma membrane bilayer. Generally P-gp substrates are large planar molecules containing

BCRP and MRP

Other significant drug transporters belonging to the ABC superfamily include those of the ABCC subfamily, i.e. MRP transporters, and the ABCG subfamily member, ABCG2/BCRP.

In epithelial cells the BCRP protein is generally expressed on the apical membranes [35], [36] and serves as an efflux transporter. The transporter has a broad range of substrates extending beyond anti-cancer agents to include antivirals, HMG-CoA reductase inhibitors, antibiotics and calcium-channel blockers [37]. The MRP

OCT/OCTN

The solute carrier family 22 (SLC22) includes three polyspecific organic cation transporters, OCT1, 2 and 3. The OCTs translocate a range of organic cations of differing structures in a bidirectional Na+-independent electrogenic manner. Some non-charged molecules have also been shown to be transported by OCTs. OCTs can be inhibited by a large number of compounds, many of which do not serve as substrates in their own right. The substrate specificities of the different OCTs broadly overlap [50],

OAT/OATP

Organic anion transporters (OATs) belong to the solute carrier family 22 (SLC22), while the organic anion transporting polypeptides (OATPs) belong to the solute carrier family SLC21/SLCO. Evidence is lacking for the spatial protein expression and functionality within the intact lung for OATs and OATPs.

PEPT1/PEPT2

PEPT1 and PEPT2 are proton-oligopeptide co-transporters belonging to solute carrier family 15 (SLC15). They are di- and tri-peptide transporters but with a broad substrate capacity such that many small peptide-like drugs, as well as non-peptidic drugs, can also serve as substrates, for example β-lactam antibiotics, ACE inhibitors and antivirals, e.g. valacyclovir.

Correlation between in-vitro and ex-vivo or in-vivo lung models

It is increasingly clear that at least for some biological barriers, notably the intestine, data from in-vitro models has applicability in predicting in-vivo drug absorption characteristics [74], [75]. For example, Varma et al. [76] reported the permeability of MCDK-MDR1 cell monolayers to an extensive range of P-gp substrates and P-gp non-substrates and showed that in-vitro permeability data when coupled with drug characteristics from the Biopharmaceutics Classification System (BCS) improves

Genetic polymorphism, disease and the lung

Single nucleotide polymorphisms (SNPs) are the most common type of genetic dissimilarity between individuals and can display ethnic and disease associations. While many of the reported genomic SNPs are not associated with altered protein function, there is increasing evidence that some SNPs can lead to altered drug absorption and disposition, with the vast majority of such studies that demonstrate functional impact undertaken in hepatic, renal, intestinal or brain microvasculature tissues. It

Conclusion and areas for further investigation

The challenges are not only to gain consensus upon the spatial expression of drug transporters within the lung tissue but to determine the circumstances under which such transporters may impact upon drug absorption and disposition, and the potential for drugs to modulate the normal physiological functioning of these transporters. Given the often low dose drug administrations into the airway or low concentrations of drugs in serum, it is likely that whatever the exposure surface, i.e. airway or

Acknowledgements

MG would like to acknowledge collaborations and discussions with Chris Edwards, John Keogh, and Graham Somers, from GSK.

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