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

• Main Authors: Martina Medvedíková (Author), Václav Ranc (Author), Ján Vančo (Author), Zdeněk Trávníček (Author), Pavel Anzenbacher (Author)
• Format: Book
• Published: MDPI AG, 2023-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

The effects of two anticancer active copper(II) mixed-ligand complexes of the type [Cu(qui)(mphen)]Y·H₂O, where Hqui = 2-phenyl-3-hydroxy- 1H-quinolin-4-one, mphen = bathophenanthroline, and Y = NO₃ (complex <b>1</b>) or BF₄ (complex <b>2</b>) 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 (IC₅₀ values were 2.46 and 4.88 μM), CYP2C9 (IC₅₀ values were 16.34 and 37.25 μM), and CYP2C19 (IC₅₀ 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 <b>1</b> and <b>2</b> 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.

Item Description

10.3390/pharmaceutics15041314
1999-4923