Methotrexate-based ionic liquid as a potent anticancer drug for oral delivery: In vivo pharmacokinetics, biodistribution, and antitumor efficacy
| Autor: | Rahman Md Moshikur, Rie Wakabayashi, Masahiro Goto, Muhammad Moniruzzaman, Korban Ali |
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| Rok vydání: | 2021 |
| Předmět: |
musculoskeletal diseases
Drug Biodistribution media_common.quotation_subject Pharmaceutical Science Ionic Liquids Antineoplastic Agents Pharmacology Mice Pharmacokinetics immune system diseases Oral administration medicine Animals heterocyclic compounds Tissue Distribution Proline skin and connective tissue diseases media_common chemistry.chemical_classification Chemistry Amino acid Bioavailability Methotrexate Solubility medicine.drug |
| Zdroj: | International journal of pharmaceutics. 608 |
| ISSN: | 1873-3476 |
| Popis: | 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 (IL[ProEt][MTX]) had 4.6-fold higher oral bioavailability than MTX sodium, followed by aspartic diethyl ester MTX, IL[TBP][MTX], IL[Cho][MTX], and IL[TMA][MTX]. The peak plasma concentration, elimination half-life, area under the plasma concentration, mean absorption time, and body clearance of IL[ProEt][MTX] 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 IL[ProEt][MTX] 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 IL[ProEt][MTX] 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. |
| Databáze: | OpenAIRE |
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