Publication in Pharmaceutics

In Vitro Cytochrome P450 Interaction Profile and ADME Characterisation of Gold(I)–Triphenylphosphine Complexes with 6-Alkoxy-9-Deazapurine Ligands

Authors: Martina Medvedíková, Ján Vančo, Zdeněk Trávníček, Pavel Anzenbacher

Full-text: https://doi.org/10.3390/pharmaceutics18050599

 

In this study, two gold(I)–triphenylphosphine complexes bearing 6-alkoxy-9-deazapurine ligands were comprehensively evaluated for their in vitro pharmacokinetic properties and interactions with major drug-metabolising CYP450 enzymes. Both complexes showed high chemical and plasma stability, moderate microsomal stability, substantial plasma protein binding, and low passive membrane permeability. Kinetic analyses established a noncompetitive inhibition mechanism for both complexes, and UV–Vis difference spectroscopy confirmed substrate-like, reversible binding within the hydrophobic active-site cavity, without direct metal–heme coordination. ITC measurements provided thermodynamic evidence for strong, spontaneous, and enthalpically driven binding to CYP3A4, fully consistent with the functional and spectroscopic data. These findings enhance understanding of the metabolic liabilities and potential drug interactions of gold(I) complexes and provide a valuable basis for their further rational development as metal-based bioactive agents.