title: Absorption of ipratropium and l-carnitine into the pulmonary circulation of the ex-vivo rat lung is driven by passive processes rather than active uptake by OCT/OCTN transporters.
abstract: The organic cation transporters OCT and OCTN have been reported to play a significant role in the cellular uptake of substrates within in vitro lung cells. However, no studies to date have investigated the effect of these transporters upon transepithelial absorption of substrates into the pulmonary circulation. We investigated the contribution of OCT and OCTN transporters to total pulmonary absorption of l-carnitine and the anti-muscarinic drug, ipratropium, across an intact isolated perfused rat lung (IPRL). The results obtained from the IPRL were contrasted with active transport in vitro using three human pulmonary cell lines and primary rat alveolar epithelial cells. Ex-vivo studies showed that OCT/OCTN transporters do not play a role in the overall pulmonary absorption of l-carnitine or ipratropium, as evidenced by the effect of chemical inhibition of these transporters upon pulmonary absorption. In contrast, in vitro studies showed that OCT/OCTN transporters play a significant role in cellular accumulation of substrates with preferential uptake of ipratropium by OCTs, and of l-carnitine uptake by OCTNs. The results show that in vitro uptake studies cannot be predictive of airway to blood absorption in vivo. Nevertheless, localised submucosal pulmonary concentrations of inhaled drugs and their pulmonary pharmacodynamic profiles may be influenced by OCT/OCTN transport activity.
authors.affiliation: School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Wales CF10 3NB, United Kingdom.
authors.forename: Ghaith
authors.initials: G
authors.lastname: Al-Jayyoussi
authors.affiliation: School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Wales CF10 3NB, United Kingdom.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Price
authors.affiliation: School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Wales CF10 3NB, United Kingdom.
authors.forename: Katharina
authors.initials: K
authors.lastname: Kreitmeyr
authors.affiliation: JPK Consulting, Hitchin, Hertfordshire, SG5 1XG, United Kingdom.
authors.forename: John P
authors.initials: JP
authors.lastname: Keogh
authors.affiliation: School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Wales CF10 3NB, United Kingdom.
authors.forename: Mathew W
authors.initials: MW
authors.lastname: Smith
authors.affiliation: School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Wales CF10 3NB, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Gumbleton
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich Research Park, NR4 7TJ, United Kingdom. Electronic address: christopher.j.morris@uea.ac.uk.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Morris
mesh_terms: D000818:Animals; D002331:Carnitine / Q000493:pharmacokinetics*; D002352:Carrier Proteins / Q000502:physiology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D009241:Ipratropium / Q000493:pharmacokinetics*; D008168:Lung / Q000378:metabolism*; D008565:Membrane Proteins / Q000502:physiology; D027701:Organic Cation Transport Proteins / Q000502:physiology*; D011652:Pulmonary Circulation; D051381:Rats; D000074058:Solute Carrier Family 22 Member 5; D000070590:Solute Carrier Proteins; D027981:Symporters
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D027701:Organic Cation Transport Proteins; C000705567:Slc22a4 protein, rat; C115441:Slc22a5 protein, rat; D000074058:Solute Carrier Family 22 Member 5; D000070590:Solute Carrier Proteins; D027981:Symporters; D009241:Ipratropium; D002331:Carnitine
keywords: Isolated perfused rat lung (IPRL); Lung; Organic cation transporters, OCT1, OCT2, OCT3, OCTN; Pulmonary absorption; SLC22; Transporters