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Article

Pharmacokinetics-Driven Evaluation of the Antioxidant Activity of Curcuminoids and Their Major Reduced Metabolites—A Medicinal Chemistry Approach

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Institute of Pharmacognosy, Interdisciplinary Centre of Excellence, University of Szeged, H-6720 Szeged, Hungary
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Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Hungary
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Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010 Graz, Austria
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Department of Chemical and Environmental Process Engineering, Budapest University of Technology and Economics, H-1111 Budapest, Hungary
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Department of Pharmacodynamics and Biopharmacy, University of Szeged, H-6720 Szeged, Hungary
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Interdisciplinary Centre of Natural Products, University of Szeged, H-6720 Szeged, Hungary
*
Authors to whom correspondence should be addressed.
Academic Editors: Bruno Botta, Cinzia Ingallina, Andrea Calcaterra and Deborah Quaglio
Molecules 2021, 26(12), 3542; https://doi.org/10.3390/molecules26123542
Received: 30 April 2021 / Revised: 1 June 2021 / Accepted: 2 June 2021 / Published: 10 June 2021
Curcuminoids are the main bioactive components of the well-known Asian spice and traditional medicine turmeric. Curcuminoids have poor chemical stability and bioavailability; in vivo they are rapidly metabolized to a set of bioreduced derivatives and/or glucuronide and sulfate conjugates. The reduced curcuminoid metabolites were also reported to exert various bioactivities in vitro and in vivo. In this work, we aimed to perform a comparative evaluation of curcuminoids and their hydrogenated metabolites from a medicinal chemistry point of view, by determining a set of key pharmacokinetic parameters and evaluating antioxidant potential in relation to such properties.Reduced metabolites were prepared from curcumin and demethoxycurcumin through continuous-flow hydrogenation. As selected pharmacokinetic parameters, kinetic solubility, chemical stability, metabolic stability in human liver microsomes, and parallel artificial membrane permeability assay (PAMPA)-based gastrointestinal and blood-brain barrier permeability were determined. Experimentally determined logP for hydrocurcumins in octanol-water and toluene-water systems provided valuable data on the tendency for intramolecular hydrogen bonding by these compounds. Drug likeness of the compounds were further evaluated by a in silico calculations. Antioxidant properties in diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and oxygen radical absorbance capacity (ORAC) assays were comparatively evaluated through the determination of ligand lipophilic efficiency (LLE). Our results showed dramatically increased water solubility and chemical stability for the reduced metabolites as compared to their corresponding parent compound. Hexahydrocurcumin was found the best candidate for drug development based on a complex pharmacokinetical comparison and high LLE values for its antioxidant properties. Development of tetrahydrocurcumin and tetrahydro-demethoxycurcumin would be limited by their very poor metabolic stability, therefore such an effort would rely on formulations bypassing first-pass metabolism. View Full-Text
Keywords: curcumin metabolite; continuous-flow hydrogenation; physicochemical characterization; gastrointestinal and blood-brain barrier penetration; pharmacokinetics; metabolism curcumin metabolite; continuous-flow hydrogenation; physicochemical characterization; gastrointestinal and blood-brain barrier penetration; pharmacokinetics; metabolism
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MDPI and ACS Style

Girst, G.; Ötvös, S.B.; Fülöp, F.; Balogh, G.T.; Hunyadi, A. Pharmacokinetics-Driven Evaluation of the Antioxidant Activity of Curcuminoids and Their Major Reduced Metabolites—A Medicinal Chemistry Approach. Molecules 2021, 26, 3542. https://doi.org/10.3390/molecules26123542

AMA Style

Girst G, Ötvös SB, Fülöp F, Balogh GT, Hunyadi A. Pharmacokinetics-Driven Evaluation of the Antioxidant Activity of Curcuminoids and Their Major Reduced Metabolites—A Medicinal Chemistry Approach. Molecules. 2021; 26(12):3542. https://doi.org/10.3390/molecules26123542

Chicago/Turabian Style

Girst, Gábor, Sándor B. Ötvös, Ferenc Fülöp, György T. Balogh, and Attila Hunyadi. 2021. "Pharmacokinetics-Driven Evaluation of the Antioxidant Activity of Curcuminoids and Their Major Reduced Metabolites—A Medicinal Chemistry Approach" Molecules 26, no. 12: 3542. https://doi.org/10.3390/molecules26123542

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