Ion-Pairing with Spermine Targets Theophylline to the Lungs via the Polyamine Transport System

Faiza Benaouda, Stuart A. Jones*, Jasminder Chana, Benedetta M. Dal Corno, David J. Barlow, Robert C. Hider, Clive P. Page, Ben Forbes

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)
285 Downloads (Pure)


Certain xenobiotics, such as paraquat, are sequestered into the lungs from the systemic circulation by the polyamine transporter system (PTS). The aim of this study was to investigate whether ion-pairing a drug (theophylline) with a PTS substrate (spermine) provides a means of using this active transport mechanism to target drug delivery to the lungs. Fourier transform infrared spectroscopy showed that two of the amine groups of spermine interact with C-N7 and C6O of theophylline, leaving two free amines to interact with the PTS. In A549 cells, which possess a functional PTS (spermidine Km and Vmax, 0.6 ± 0.3 μM and 1.8 ± 0.3 pmol·min-1 per 105 cells, respectively), uptake of the theophylline-spermine ion-pair was increased 1.8-fold compared to free theophylline at 37 °C, but not at 4 °C. In an isolated perfused rat lung model (IPL) a 3.6-fold increase in lung theophylline concentration was observed after vascular administration of the ion-pair compared to free theophylline. Theophylline was cleared from the IPL with similar kinetics irrespective of whether it was delivered as the free drug or an ion-pair, although lung levels remained elevated after washout following delivery as an ion-pair. In vitro simulation of the theophylline-spermine break down demonstrated that a drop in pH from 9.6 to 7.4, such as that undergone by the ion-pair in biological matrices, induces rapid and almost complete dissociation of the ion-paired species. However, infusion of the ion-pair formulations via the vasculature provides almost immediate delivery to the pulmonary capillary bed permitting PTS-mediated active sequestering of ion-paired theophylline into the lungs.

Original languageEnglish
Pages (from-to)861-870
Number of pages10
JournalMolecular Pharmaceutics
Issue number3
Early online date8 Jan 2018
Publication statusPublished - 5 Mar 2018


  • A549 drug-targeting
  • active uptake
  • ion pair
  • isolated perfused lung
  • lung
  • polyamine
  • theophylline


Dive into the research topics of 'Ion-Pairing with Spermine Targets Theophylline to the Lungs via the Polyamine Transport System'. Together they form a unique fingerprint.

Cite this