Pharmacokinetics-Driven Evaluation of the Antioxidant Activity of Curcuminoids and Their Major Reduced Metabolites—A Medicinal Chemistry Approach
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 reduce...
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| Format: | Article |
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MDPI AG
2021-06-01
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| Series: | Molecules |
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| author | Gábor Girst Sándor B. Ötvös Ferenc Fülöp György T. Balogh Attila Hunyadi |
| author_facet | Gábor Girst Sándor B. Ötvös Ferenc Fülöp György T. Balogh Attila Hunyadi |
| author_sort | Gábor Girst |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T10:31:58Z |
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| id | doaj.art-269a57e28cee4cf0b0b468c7bc6a392a |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T10:31:58Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
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| series | Molecules |
| spelling | doaj.art-269a57e28cee4cf0b0b468c7bc6a392a2023-11-21T23:32:34ZengMDPI AGMolecules1420-30492021-06-012612354210.3390/molecules26123542Pharmacokinetics-Driven Evaluation of the Antioxidant Activity of Curcuminoids and Their Major Reduced Metabolites—A Medicinal Chemistry ApproachGábor Girst0Sándor B. Ötvös1Ferenc Fülöp2György T. Balogh3Attila Hunyadi4Institute of Pharmacognosy, Interdisciplinary Centre of Excellence, University of Szeged, H-6720 Szeged, HungaryInstitute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, HungaryInstitute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, HungaryDepartment of Chemical and Environmental Process Engineering, Budapest University of Technology and Economics, H-1111 Budapest, HungaryInstitute of Pharmacognosy, Interdisciplinary Centre of Excellence, University of Szeged, H-6720 Szeged, HungaryCurcuminoids 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.https://www.mdpi.com/1420-3049/26/12/3542curcumin metabolitecontinuous-flow hydrogenationphysicochemical characterizationgastrointestinal and blood-brain barrier penetrationpharmacokineticsmetabolism |
| spellingShingle | Gábor Girst Sándor B. Ötvös Ferenc Fülöp György T. Balogh Attila Hunyadi Pharmacokinetics-Driven Evaluation of the Antioxidant Activity of Curcuminoids and Their Major Reduced Metabolites—A Medicinal Chemistry Approach Molecules curcumin metabolite continuous-flow hydrogenation physicochemical characterization gastrointestinal and blood-brain barrier penetration pharmacokinetics metabolism |
| title | Pharmacokinetics-Driven Evaluation of the Antioxidant Activity of Curcuminoids and Their Major Reduced Metabolites—A Medicinal Chemistry Approach |
| title_full | Pharmacokinetics-Driven Evaluation of the Antioxidant Activity of Curcuminoids and Their Major Reduced Metabolites—A Medicinal Chemistry Approach |
| title_fullStr | Pharmacokinetics-Driven Evaluation of the Antioxidant Activity of Curcuminoids and Their Major Reduced Metabolites—A Medicinal Chemistry Approach |
| title_full_unstemmed | Pharmacokinetics-Driven Evaluation of the Antioxidant Activity of Curcuminoids and Their Major Reduced Metabolites—A Medicinal Chemistry Approach |
| title_short | Pharmacokinetics-Driven Evaluation of the Antioxidant Activity of Curcuminoids and Their Major Reduced Metabolites—A Medicinal Chemistry Approach |
| title_sort | pharmacokinetics driven evaluation of the antioxidant activity of curcuminoids and their major reduced metabolites a medicinal chemistry approach |
| topic | curcumin metabolite continuous-flow hydrogenation physicochemical characterization gastrointestinal and blood-brain barrier penetration pharmacokinetics metabolism |
| url | https://www.mdpi.com/1420-3049/26/12/3542 |
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