title: Correlation of Organic Cation/Carnitine Transporter 1 and Multidrug Resistance-Associated Protein 1 Transport Activities With Protein Expression Levels in Primary Cultured Human Tracheal, Bronchial, and Alveolar Epithelial Cells.
abstract: Understanding how transporters contribute to the distribution of inhaled drugs in the lung is important for the discovery and development of such drugs. Protein expression levels may be useful to predict and understand drug distribution. As previously reported, organic cation/carnitine transporter 1 (OCTN1) and multidrug resistance-associated protein 1 (MRP1) have higher levels of protein expression among transporters in primary cultured human lung cells. Nevertheless, it is unclear to what extent transport activity correlates with transporter protein expression. The purpose is to evaluate whether differences in OCTN1 and MRP1 protein expression govern the respective transport activity in primary cultured human lung cells. The model substrates of 4-[4-(dimethylamino) styryl]-N-methylpyridinium iodide (ASP(+)) and carboxy-dichlorofluorescein (CDF) for OCTN1 and MRP1, respectively, were used in the lung cells from five donors. Significant correlation was found between the kinetic parameter Vmax for ASP(+) and OCTN1 protein expression in plasma membrane of tracheal, bronchial, and alveolar cells (r(2) = 0.965, 0.834, and 0.877, respectively), and between the efflux of CDF and MRP1 protein expression in plasma membrane of tracheal, bronchial, and alveolar cells (r(2) = 0.800, 0.904, and 0.790, respectively). These findings suggest that OCTN1 and MRP1 protein concentrations are determinants for drug distribution in the lung.
authors.affiliation: Nippon Boehringer Ingelheim, Pharmacokinetics and Nonclinical Safety, Kobe, Hyogo 650-0047, Japan; Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan. Electronic address: atsushi.sakamoto@boehringer-ingelheim.com.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sakamoto
authors.affiliation: Nippon Boehringer Ingelheim, Pharmacokinetics and Nonclinical Safety, Kobe, Hyogo 650-0047, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Nippon Boehringer Ingelheim, Pharmacokinetics and Nonclinical Safety, Kobe, Hyogo 650-0047, Japan.
authors.forename: Takehisa
authors.initials: T
authors.lastname: Matsumaru
authors.affiliation: Nippon Boehringer Ingelheim, Pharmacokinetics and Nonclinical Safety, Kobe, Hyogo 650-0047, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Yamamura
authors.affiliation: Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchida
authors.affiliation: Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Tachikawa
authors.affiliation: Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Terasaki
mesh_terms: D001980:Bronchi / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000096:biosynthesis / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism*; D027981:Symporters; D014132:Trachea / Q000166:cytology / Q000378:metabolism*
chemical_list: D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027701:Organic Cation Transport Proteins; D027981:Symporters; C109807:SLC22A4 protein, human; C421109:multidrug resistance-associated protein 1
keywords: ABC transporters; drug transport; individualized drug therapy; mass spectrometry; membrane transporter; multidrug resistance-associated proteins; organic cation transporters (OCT); proteomics; pulmonary drug delivery; targeted drug delivery