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. 2023 May;40(5):1299-1310.
doi: 10.1007/s11095-023-03500-5. Epub 2023 Apr 20.

Cationic Ester Prodrugs of Curcumin with N,N-dimethyl Amino Acid Promoieties Improved Poor Water Solubility and Intestinal Absorption

Mariko Hirano-Kusuda  1 , Shuichi Setoguchi  1 , Mitsuhisa Koga  1 , Shotaro Goto  1 , Ayano Yamada  1 , Daisuke Watase  1 , Nami Nagata-Akaho  1 , Yoshiharu Karube  1 , Kazuhisa Matsunaga  2 , Jiro Takata  1
Affiliations

Cationic Ester Prodrugs of Curcumin with N,N-dimethyl Amino Acid Promoieties Improved Poor Water Solubility and Intestinal Absorption

Mariko Hirano-Kusuda et al. Pharm Res. 2023 May.

Abstract

Purpose: Although curcumin (Cur) has powerful pharmacological effects, its use in medicine has not been established yet. The oral bioavailability (BA) of Cur is limited because of its poor water solubility. The purpose of this study was to confirm whether cationic N,N-dimethyl amino acid esters of Cur could act as prodrugs and improve its water solubility and oral bioavailability.

Methods: Two N,N-dimethyl amino acid esters of Cur were synthesized. The hydrolysis profile of the esters was evaluated using rat and human microsomes. A pharmacokinetic study after oral administration of the Cur ester derivatives was performed in rats and compared to the administration of suspended or dissolved Cur formulation. The anti-inflammatory effects of the Cur derivatives were evaluated using macrophage RAW 264.7 stimulated with lipopolysaccharide.

Results: Cur ester derivatives showed > 200 mM water solubility. The derivatives were reconverted to the parent compound (Cur) after cleavage of the ester bonds by microsomal esterase, indicating that the compounds could act as Cur prodrugs. The Cur prodrugs enhanced the absolute oral bioavailability of Cur by a 9- and threefold increase of suspended and dissolved Cur administration, respectively, thereby improving intestinal absorption. Cur prodrugs strongly attenuated COX2, iNOS, and ERK phosphorylation.

Conclusions: The cationic N,N-dimethyl amino acid ester prodrugs of Cur improved the water solubility of Cur and enhanced oral bioavailability in rats. These Cur prodrugs may be good candidates for developing medicinal options previously unavailable due to the poor water solubility and oral BA of Cur.

Keywords: bioavailability; curcumin; drug delivery system; prodrug; rat.

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