Methotrexate-based ionic liquid as a potent anticancer drug for oral delivery: In vivo pharmacokinetics, biodistribution, and antitumor efficacy

Moshikur RM 1 , Ali MK 2 , Wakabayashi R 3 , Moniruzzaman M 4 , Goto M 5

Affiliations 

  • 1 Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan. Electronic address: rahman.md.moshikur.064@m.kyushu-u.ac.jp
  • 2 Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan; Department of Chemistry, Jashore University of Science and Technology, Jashore 7408, Bangladesh. Electronic address: mk.liton@just.edu.bd
  • 3 Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan; Advanced Transdermal Drug Delivery System Center, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan. Electronic address: wakabayashi.rie.122@m.kyushu-u.ac.jp
  • 4 Department of Chemical Engineering, Universiti Teknologi PETRONAS, 32610 Seri Iskandar, Perak, Malaysia. Electronic address: m.moniruzzaman@utp.edu.my
  • 5 Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan; Advanced Transdermal Drug Delivery System Center, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan; Division of Biotechnology, Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan. Electronic address: m-goto@mail.cstm.kyushu-u.ac.jp
Int J Pharm, 2021 Oct 25;608:121129.
PMID: 34562557 DOI: 10.1016/j.ijpharm.2021.121129

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 (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 

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