title: Evaluation of the physicochemical and biopharmaceutical properties of fluoro-indomethacin.
abstract: Drug nanocarriers have shown great potential in therapy and as diagnostic probes, e.g. in imaging of cancer and inflammation. Imaging can be applied to localize the carrier or the drug itself in the body and/or tissues. In this particular case it is important that drug molecules have the characteristics for possible detection, e.g. after modification with positron emission tomography compliant radioisotopes, without affecting their pharmacological behavior. In order to easily and efficiently follow the ADME profile of the drug after loaded into nanocarriers, the drug can be radiolabelled with, e.g. 18F-label, in order to assess its biodistribution after enteral and parenteral administration in rats. However, this is only possible if the derivative compound behaves similarly to the parent drug compound. In this study, indomethacin (a poorly water-soluble drug) was chosen as a model compound and aimed to evaluate the physicochemical and biopharmaceutical properties of an analog of indomethacin (IMC), fluoro-indomethacin (F-IMC). Although some of the physicochemical and biopharmaceutical properties of IMC are already known, in order to establish a feasible comparison between IMC and F-IMC, the behavior of the former was also investigated in the same conditions as for F-IMC. In this context, both IMC and F-IMC were thermally and morphologically studied. Furthermore, the following properties were also studied for both compounds: pKa and logP, solubility and dissolution profiles at physiological pH values, and toxicity at different concentrations in Caco-2 cells. Finally, the transport across Caco- 2 monolayers of the IMC and F-IMC at physiological pH range was also investigated. The results obtained showed similar values in pKalogP, solubility, dissolution, cytotoxicity, and permeability for both compounds. Thus, there might be strong evidence that both IMC and F-IMC should have a similar ADME behavior and profiles in vivo. The results provide fundamental tools and ideas for further research with nanocarriers of 18F-IMC.
authors.affiliation: Department of Drug Sciences, University of Pavia, Viale Tarameli 12, 27100 Pavia, Italy.
authors.forename: Michela M
authors.initials: MM
authors.lastname: Mori
authors.forename: Anu J
authors.initials: AJ
authors.lastname: Airaksinen
authors.forename: Jouni T
authors.initials: JT
authors.lastname: Hirvonen
authors.forename: Hélder A
authors.initials: HA
authors.lastname: Santos
authors.forename: Carla M
authors.initials: CM
authors.lastname: Caramella
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D001692:Biological Transport; D018938:Caco-2 Cells; D005240:Feasibility Studies; D005461:Fluorine / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007213:Indomethacin / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D010539:Permeability; D012995:Solubility; D014018:Tissue Distribution; D018675:Toxicity Tests
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005461:Fluorine; D007213:Indomethacin