In Vitro Cytochrome P450 Interaction Profile and ADME Characterisation of Gold(I)-Triphenylphosphine Complexes with...

Background/Objectives: Gold(I) complexes are promising bioactive agents with anticancer and anti-inflammatory potential. This study evaluated cytochrome P450 (CYP) interactions and in vitro pharmacokinetic properties of two Au(I)-triphenylphosphine complexes bearing 6-alkoxy-9-deazapurine ligands. Methods: Complexes [Au(HL_1,2)(PPh₃)] (HL₁ = 6-isopropyloxy-9-deazapurine, complex 1; HL₂ = 6-benzyloxy-9-deazapurine, complex 2) were investigated. Inhibition of nine human CYP isoforms was assessed in liver microsomes, and kinetics were analyzed using Dixon and Lineweaver-Burk plots. CYP binding was evaluated by UV-Vis difference spectroscopy. ADME properties (chemical/plasma stability, microsomal stability, plasma protein binding, and PAMPA permeability) were determined. Binding thermodynamics were analyzed by ITC. Results: Both complexes weakly inhibited most CYP isoforms, with stronger effects on CYP2C9 and CYP3A4/5. A non-competitive inhibition mechanism was observed, which may be related to the binding of the complexes to the substrate channels of CYP2C9 and CYP3A4, thereby limiting the active site's accessibility to the substrate, as supported by molecular docking studies. UV-Vis spectra showed type I binding with Kd values of 9.32 µM (1) and 12.64 µM (2). Both compounds showed high chemical and plasma stability (>90%), moderate microsomal stability (~60% after 60 min), high plasma protein binding (~80%), and low passive permeability. Conclusions: Au(I)-triphenylphosphine complexes with 6-alkoxy-9-deazapurine ligands exhibit moderate CYP affinity and defined pharmacokinetic profiles, supporting further preclinical evaluation.