• Corno, Benedetta M. Dal
• Page, Clive Peter
• Chana, Jasminder
• Benaouda, Faiza
• Hider, Robert C.
• Jones, Stuart
• Forbes, Ben

Abstract

<p>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 K_m and V_max, 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.</p>

Topics

• simulation
• amine
• Fourier transform infrared spectroscopy