The Differential Absorption of a Series of P-Glycoprotein Substrates in Isolated Perfused Lungs from Mdr1a/1b Genetic Knockout Mice can be Attributed to Distinct Physico-Chemical Properties: an Insight into Predicting Transporter-Mediated, Pulmonary Specific Disposition

Daniel F Price,Chris D Edwards,Mark Gumbleton,Peter J Eddershaw,Chris N Luscombe

doi:10.1007/s11095-017-2220-5

Abstract

PurposeTo examine if pulmonary P-glycoprotein (P-gp) is functional in an intact lung; impeding the pulmonary absorption and increasing lung retention of P-gp substrates administered into the airways. Using calculated physico-chemical properties alone build a predictive Quantitative Structure-Activity Relationship (QSAR) model distinguishing whether a substrate’s pulmonary absorption would be limited by P-gp or not.MethodsA panel of 18 P-gp substrates were administered into the airways of an isolated perfused mouse lung (IPML) model derived from Mdr1a/Mdr1b knockout mice. Parallel intestinal absorption studies were performed. Substrate physico-chemical profiling was undertaken. Using multivariate analysis a QSAR model was established.ResultsA subset of P-gp substrates (10/18) displayed pulmonary kinetics influenced by lung P-gp. These substrates possessed distinct physico-chemical properties to those P-gp substrates unaffected by P-gp (8/18). Differential outcomes were not related to different intrinsic P-gp transporter kinetics. In the lung, in contrast to intestine, a higher degree of non-polar character is required of a P-gp substrate before the net effects of efflux become evident. The QSAR predictive model was applied to 129 substrates including eight marketed inhaled drugs, all these inhaled drugs were predicted to display P-gp dependent pulmonary disposition.ConclusionsLung P-gp can affect the pulmonary kinetics of a subset of P-gp substrates. Physico-chemical relationships determining the significance of P-gp to absorption in the lung are different to those operative in the intestine. Our QSAR framework may assist profiling of inhaled drug discovery candidates that are also P-gp substrates. The potential for P-gp mediated pulmonary disposition exists in the clinic.

Highlights

Alongside passive processes, active or facilitative transporters may govern the permeability of biological barriers to drugs
For the Group B compounds did the deletion of Mdr1a/1b (−/−) result in significant increases (37% to 93%) in pulmonary absorption (P-values 0.003 to 0.027, Supplementary Table S3)
On the basis of the impact of P-gp upon a substrate’s absorption within the isolated perfused mouse lung (IPML) we defined the panel members as either ‘Group A’ compounds i.e. those whose pulmonary absorption was unaffected by Mdr1a/1b knockout, or ‘Group B’ compounds, i.e. those whose pulmonary absorption was limited by P-gp, absorption was increased by Mdr1a/1b knockout

Summary

Introduction

Active or facilitative transporters may govern the permeability of biological barriers to drugs. While there is increasing awareness of the range and pattern of expression of transporters within lung tissue (reviewed in [1,2]) the functional significance of transporters upon pulmonary drug disposition is less well understood. There are a number of in-vitro studies using alveolar and bronchial primary epithelial cells [4,10], or continuous lung epithelial cell lines [2,11,12], corroborating P-gp protein expression and reporting varying extents of polarised transport functionality. The impact of P-gp upon the overall pulmonary absorption and disposition of airways administered drugs is poorly understood, and requires investigation within lung models where tissue architecture and the parallel processes of passive and active clearance mechanisms from the airways are to a large extent preserved

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