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

• Published in: Pharmaceutical research 2017-12, Vol.34 (12), p.2498-2516
• Main Authors: Price, Daniel F., Luscombe, Chris N., Eddershaw, Peter J., Edwards, Chris D., Gumbleton, Mark
• Format: Article
• Language: English
• Subjects: Absorption; Analysis; Animals; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - metabolism; ATP-Binding Cassette Sub-Family B Member 4; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Chemical properties; Drug discovery; Genetic research; Genetics; Indacaterol; Intestinal absorption; Intestine; Kinetics; Lung - metabolism; Lungs; Male; Medical Law; Mice; Mice, Knockout; Multidrug resistance; Multivariate analysis; P-Glycoprotein; Pharmaceutical Preparations - chemistry; Pharmaceutical Preparations - metabolism; Pharmacology/Toxicology; Pharmacy; Physicochemical properties; Research Paper; Respiratory Tract Absorption; Rodents; Structure-activity relationships; Substrate Specificity; Substrates
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-017-2220-5

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.