title: Montelukast Disposition: No Indication of Transporter-Mediated Uptake in OATP2B1 and OATP1B1 Expressing HEK293 Cells.
abstract: Clinical studies with montelukast show variability in effect and polymorphic OATP2B1-dependent absorption has previously been implicated as a possible cause. This claim has been challenged with conflicting data and here we used OATP2B1-transfected HEK293 cells to clarify the mechanisms involved. For montelukast, no significant difference in cell uptake between HEK-OATP2B1 and empty vector cell lines was observed at pH 6.5 or pH 7.4, and no concentration-dependent uptake was detected. Montelukast is a carboxylic acid, a relatively potent inhibitor of OATP1B1, OATP1B3, and OATP2B1, and has previously been postulated to be actively transported into human hepatocytes. Using OATP1B1-transfected HEK293 cells and primary human hepatocytes in the presence of OATP inhibitors we demonstrate for the first time that active OATP-dependent transport is unlikely to play a significant role in the human disposition of montelukast.
authors.affiliation: Respiratory, Inflammation and Autoimmunity Innovative Medicine, AstraZeneca R&amp;D Gothenburg, 431 83 Mölndal, Sweden. marie.brannstrom@astrazeneca.com.
authors.forename: Marie
authors.initials: M
authors.lastname: Brännström
authors.affiliation: Drug Safety and Metabolism, AstraZeneca R&amp;D Gothenburg, 431 83 Mölndal, Sweden. par.nordell@astrazeneca.com.
authors.forename: Pär
authors.initials: P
authors.lastname: Nordell
authors.affiliation: Respiratory, Inflammation and Autoimmunity Innovative Medicine, AstraZeneca R&amp;D Gothenburg, 431 83 Mölndal, Sweden. britta.bonn@astrazeneca.com.
authors.forename: Britta
authors.initials: B
authors.lastname: Bonn
authors.affiliation: Respiratory, Inflammation and Autoimmunity Innovative Medicine, AstraZeneca R&amp;D Gothenburg, 431 83 Mölndal, Sweden. andy.davis@astrazeneca.com.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davis
authors.affiliation: Respiratory, Inflammation and Autoimmunity Innovative Medicine, AstraZeneca R&amp;D Gothenburg, 431 83 Mölndal, Sweden. anna-pia.palmgren@astrazeneca.com.
authors.forename: Anna-Pia
authors.initials: AP
authors.lastname: Palmgren
authors.affiliation: Drug Safety and Metabolism, AstraZeneca R&amp;D Gothenburg, 431 83 Mölndal, Sweden. constanze.hilgendorf@astrazeneca.com.
authors.forename: Constanze
authors.initials: C
authors.lastname: Hilgendorf
authors.affiliation: Respiratory, Inflammation and Autoimmunity Innovative Medicine, AstraZeneca R&amp;D Gothenburg, 431 83 Mölndal, Sweden. katarina.rubin@astrazeneca.com.
authors.forename: Katarina
authors.initials: K
authors.lastname: Rubin
authors.affiliation: Respiratory, Inflammation and Autoimmunity Innovative Medicine, AstraZeneca R&amp;D Gothenburg, 431 83 Mölndal, Sweden. ken.grime@astrazeneca.com.
authors.forename: Ken
authors.initials: K
authors.lastname: Grime
keywords: OATP1B1; OATP2B1; hepatic uptake; montelukast; transporters