eprintid: 14352
rev_number: 2
eprint_status: archive
userid: 1
dir: disk0/00/01/43/52
datestamp: 2023-11-10 03:28:55
lastmod: 2023-11-10 03:28:55
status_changed: 2023-11-10 01:56:41
type: article
metadata_visibility: show
creators_name: Moshikur, R.M.
creators_name: Ali, M.K.
creators_name: Wakabayashi, R.
creators_name: Moniruzzaman, M.
creators_name: Goto, M.
title: Methotrexate-based ionic liquid as a potent anticancer drug for oral delivery: In vivo pharmacokinetics, biodistribution, and antitumor efficacy
ispublished: pub
keywords: cholinium; ionic liquid; methotrexate; tetrabutylphosphonium; tetramethylammonium; unclassified drug; antineoplastic agent; methotrexate, animal experiment; animal tissue; antineoplastic activity; area under the curve; area under the moment curve; Article; biocompatibility; cancer inhibition; comparative study; controlled study; density functional theory; drug bioavailability; drug delivery system; drug solubility; drug solution; elimination half-life; female; Fourier transform infrared spectroscopy; gastrointestinal tract; high performance liquid chromatography; hydrogen bond; in vitro study; in vivo study; intracellular transport; maximum plasma concentration; mean absorption time; mouse; nonhuman; phase separation; retention time; risk assessment; stoichiometry; tissue distribution; animal; solubility, Animals; Antineoplastic Agents; Ionic Liquids; Methotrexate; Mice; Solubility; Tissue Distribution
note: cited By 10
abstract: Oral delivery of the sparingly soluble drug methotrexate (MTX) is challenging owing to its poor bioavailability and low solubility. To address this challenge, the present study reports the conversion of MTX into a series of five ionic liquids (ILs) comprising a cationic component�i.e., cholinium (Cho), tetramethylammonium (TMA), tetrabutylphosphonium (TBP), or an amino acid ester�and an anionic component�i.e., MTX. The biocompatibility, pharmacokinetics, tissue distribution, and antitumor efficacy of each MTX-based IL were investigated to determine its usefulness as a pharmaceutical. Oral administration to mice revealed that proline ethyl ester MTX (ILProEtMTX) had 4.6-fold higher oral bioavailability than MTX sodium, followed by aspartic diethyl ester MTX, ILTBPMTX, ILChoMTX, and ILTMAMTX. The peak plasma concentration, elimination half-life, area under the plasma concentration, mean absorption time, and body clearance of ILProEtMTX were significantly (p < 0.0001) higher by 1.7-, 6.2-, 4.6-, 2.5-, and 3.6-fold, respectively, than those of MTX sodium. MTX accumulation in the lungs, spleen, kidney, and gastrointestinal tract was also reduced by 5.6-, 1.8-, 1.5-, and 1.4-fold, respectively, indicating the IL formulations had lower systemic toxicity than free MTX. Mechanistic studies revealed that the ILProEtMTX solution formed spherical structures with an average size of 190 nm. This was probably responsible for its improved oral absorption performance in vivo. In vivo antitumor studies also demonstrated that ILProEtMTX suppressed tumor growth more than MTX sodium. These results suggest that MTX-based ILs provide a simple scalable approach to improving the oral bioavailability of poorly soluble MTX. © 2021 Elsevier B.V.
date: 2021
publisher: Elsevier B.V.
official_url: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85117125165&doi=10.1016%2fj.ijpharm.2021.121129&partnerID=40&md5=76e98379969219bea0d19ca3ecdf2a07
id_number: 10.1016/j.ijpharm.2021.121129
full_text_status: none
publication: International Journal of Pharmaceutics
volume: 608
refereed: TRUE
issn: 03785173
citation:   Moshikur, R.M. and Ali, M.K. and Wakabayashi, R. and Moniruzzaman, M. and Goto, M.  (2021) Methotrexate-based ionic liquid as a potent anticancer drug for oral delivery: In vivo pharmacokinetics, biodistribution, and antitumor efficacy.  International Journal of Pharmaceutics, 608.   ISSN 03785173