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

Price, Daniel F., Luscombe, Chris N., Eddershaw, Peter J., Edwards, Chris D. and Gumbleton, Mark ORCID: https://orcid.org/0000-0002-7386-311X 2017. 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. Pharmaceutical Research 34 (12) , pp. 2498-2516. 10.1007/s11095-017-2220-5

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Abstract

Purpose To 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. Methods A 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. Results A 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. Conclusions Lung 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Subjects:	R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords:	efflux . isolated perfused lung . lung .MDR, Mdr . physico-chemical . pulmonary absorption . P-glycoprotein (P-gp) . QSAR . transporter
Additional Information:	This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license
Publisher:	American Association of Pharmaceutical Scientists
ISSN:	0724-8741
Funders:	Biotechnology and Biological Sciences Research Council (BBSRC)
Date of First Compliant Deposit:	27 July 2017
Date of Acceptance:	22 June 2017
Last Modified:	05 May 2023 21:47
URI:	https://orca.cardiff.ac.uk/id/eprint/103064

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