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Highly Cytotoxic Copper(II) Mixed-Ligand Quinolinonato Complexes: Pharmacokinetic Properties and Interactions with Drug Metabolizing Cytochromes P450

The effects of two anticancer active copper(II) mixed-ligand complexes of the type [Cu(qui)(mphen)]Y·H(2)O, where Hqui = 2-phenyl-3-hydroxy- 1H-quinolin-4-one, mphen = bathophenanthroline, and Y = NO(3) (complex 1) or BF(4) (complex 2) on the activities of different isoenzymes of cytochrome P450 (CY...

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Autores principales: Medvedíková, Martina, Ranc, Václav, Vančo, Ján, Trávníček, Zdeněk, Anzenbacher, Pavel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10146558/
https://www.ncbi.nlm.nih.gov/pubmed/37111801
http://dx.doi.org/10.3390/pharmaceutics15041314
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author Medvedíková, Martina
Ranc, Václav
Vančo, Ján
Trávníček, Zdeněk
Anzenbacher, Pavel
author_facet Medvedíková, Martina
Ranc, Václav
Vančo, Ján
Trávníček, Zdeněk
Anzenbacher, Pavel
author_sort Medvedíková, Martina
collection PubMed
description The effects of two anticancer active copper(II) mixed-ligand complexes of the type [Cu(qui)(mphen)]Y·H(2)O, where Hqui = 2-phenyl-3-hydroxy- 1H-quinolin-4-one, mphen = bathophenanthroline, and Y = NO(3) (complex 1) or BF(4) (complex 2) on the activities of different isoenzymes of cytochrome P450 (CYP) have been evaluated. The screening revealed significant inhibitory effects of the complexes on CYP3A4/5 (IC(50) values were 2.46 and 4.88 μM), CYP2C9 (IC(50) values were 16.34 and 37.25 μM), and CYP2C19 (IC(50) values were 61.21 and 77.07 μM). Further, the analysis of mechanisms of action uncovered a non-competitive type of inhibition for both the studied compounds. Consequent studies of pharmacokinetic properties proved good stability of both the complexes in phosphate buffer saline (>96% stability) and human plasma (>91% stability) after 2 h of incubation. Both compounds are moderately metabolised by human liver microsomes (<30% after 1 h of incubation), and over 90% of the complexes bind to plasma proteins. The obtained results showed the potential of complexes 1 and 2 to interact with major metabolic pathways of drugs and, as a consequence of this finding, their apparent incompatibility in combination therapy with most chemotherapeutic agents.
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spelling pubmed-101465582023-04-29 Highly Cytotoxic Copper(II) Mixed-Ligand Quinolinonato Complexes: Pharmacokinetic Properties and Interactions with Drug Metabolizing Cytochromes P450 Medvedíková, Martina Ranc, Václav Vančo, Ján Trávníček, Zdeněk Anzenbacher, Pavel Pharmaceutics Article The effects of two anticancer active copper(II) mixed-ligand complexes of the type [Cu(qui)(mphen)]Y·H(2)O, where Hqui = 2-phenyl-3-hydroxy- 1H-quinolin-4-one, mphen = bathophenanthroline, and Y = NO(3) (complex 1) or BF(4) (complex 2) on the activities of different isoenzymes of cytochrome P450 (CYP) have been evaluated. The screening revealed significant inhibitory effects of the complexes on CYP3A4/5 (IC(50) values were 2.46 and 4.88 μM), CYP2C9 (IC(50) values were 16.34 and 37.25 μM), and CYP2C19 (IC(50) values were 61.21 and 77.07 μM). Further, the analysis of mechanisms of action uncovered a non-competitive type of inhibition for both the studied compounds. Consequent studies of pharmacokinetic properties proved good stability of both the complexes in phosphate buffer saline (>96% stability) and human plasma (>91% stability) after 2 h of incubation. Both compounds are moderately metabolised by human liver microsomes (<30% after 1 h of incubation), and over 90% of the complexes bind to plasma proteins. The obtained results showed the potential of complexes 1 and 2 to interact with major metabolic pathways of drugs and, as a consequence of this finding, their apparent incompatibility in combination therapy with most chemotherapeutic agents. MDPI 2023-04-21 /pmc/articles/PMC10146558/ /pubmed/37111801 http://dx.doi.org/10.3390/pharmaceutics15041314 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Medvedíková, Martina
Ranc, Václav
Vančo, Ján
Trávníček, Zdeněk
Anzenbacher, Pavel
Highly Cytotoxic Copper(II) Mixed-Ligand Quinolinonato Complexes: Pharmacokinetic Properties and Interactions with Drug Metabolizing Cytochromes P450
title Highly Cytotoxic Copper(II) Mixed-Ligand Quinolinonato Complexes: Pharmacokinetic Properties and Interactions with Drug Metabolizing Cytochromes P450
title_full Highly Cytotoxic Copper(II) Mixed-Ligand Quinolinonato Complexes: Pharmacokinetic Properties and Interactions with Drug Metabolizing Cytochromes P450
title_fullStr Highly Cytotoxic Copper(II) Mixed-Ligand Quinolinonato Complexes: Pharmacokinetic Properties and Interactions with Drug Metabolizing Cytochromes P450
title_full_unstemmed Highly Cytotoxic Copper(II) Mixed-Ligand Quinolinonato Complexes: Pharmacokinetic Properties and Interactions with Drug Metabolizing Cytochromes P450
title_short Highly Cytotoxic Copper(II) Mixed-Ligand Quinolinonato Complexes: Pharmacokinetic Properties and Interactions with Drug Metabolizing Cytochromes P450
title_sort highly cytotoxic copper(ii) mixed-ligand quinolinonato complexes: pharmacokinetic properties and interactions with drug metabolizing cytochromes p450
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10146558/
https://www.ncbi.nlm.nih.gov/pubmed/37111801
http://dx.doi.org/10.3390/pharmaceutics15041314
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