Pharmacokinetic investigation of hydrogenated natural curcumin metabolites

Curcuminoids are the main bioactive components of the well-known Asian spice and traditional medicine, turmeric [1]. These compounds have poor bioavailability, in vivo they undergo a rapid metabolism, and bioreduced derivatives are among their main in vivo metabolites. These metabolites were also reported to exert various bioactivities in vitro and in vivo [2]. They can be synthetized by batch hydrogenation, however this method has low selectivity [3].

Our objective was to develop a procedure to selectively obtain curcuminoids with different levels of saturation by using a continuous flow hydrogenation reactor. Furthermore, we aimed to evaluate pharmacokinetic properties of the prepared metabolites, such as kinetic solubility, chemical and metabolic stability, and their gastrointestinal and blood-brain barrier permeability with parallel artificial membrane permeability assay (PAMPA).

To this end, we achieved high selectivity in preparing hexahydrocurcumin. The pharmacokinetic tests showed that the reduced metabolites have dramatically increased water solubility and chemical stability as compared to that of curcumin. The metabolic rate by human liver microsomes followed the tetrahydrocurcumin > curcumin ~ hexahydrocurcumin ≫ octahydrocurcumin order. Curcumin showed negligible BBB and GI penetration, similarly to hexahydrocurcumin, tetrahydrocurcumin was however largely superior in this regard. Our results show better bioavailability and pharmacokinetic properties for some hydrogenated curcuminoid derivatives as compared to those of curcumin.

 

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Acknowledgments

The NKFIH, Hungary (K119770), the János Bolyai fellowship of the Hungarian Academy of Sciences, the UNKP-18-4 New National Excellence Program, and the Kálmán Szász Prize are acknowledged.

• References

• 1 Nelson KM, Dahlin JL, Bisson J, Graham J, Pauli GF. The Essential Medicinal Chemistry of Curcumin. J Med Chem 2017; 60: 1620-1637.
• 2 Hunyadi A. The mechanism(s) of action of antioxidants: From scavenging reactive oxygen/nitrogen species to redox signaling and the generation of bioactive secondary metabolites. Med Res Rev 2019;
• 3 Sreeraj G, Joby J, Robin G. Kinetic Studies on the Hydrogenation of Curcuminoids Isolated from Curcuma Longa by LC/MS. Res J Chem Sci 2015; 5: 33-36.