In Vitro Interaction of Binuclear Copper Complexes with Liver Drug-Metabolizing Cytochromes P450.

Two copper(II) mixed ligand complexes with dicarboxylate bridges were prepared and studied, namely [Cu(2)(μ-fu)(pmdien)(2)(H(2)O)(2)](ClO(4))(2) (complex No. 5) and [Cu(2)(μ-dtdp)(pmdien)(2)(H(2)O)(2)](ClO(4))(2) (complex No. 6), where H(2)fu = fumaric acid, pmdien = N,N,N',N″,N″ pentamethyldiethylenetriamine, and H(2)dtdp = 3,3'-dithiodipropionic acid. The copper atoms are coordinated in the same mode by the tridentate pmdien ligand and oxygen of water molecules, and they only differ in the dicarboxylate bridge. This work is focused on the study of the inhibitory effect of these potential antimicrobial drugs on the activity of the most important human liver drug-metabolizing enzymes, cytochromes P450 (CYP), especially their forms CYP2C8, CYP2C19, and CYP3A4. The obtained results allow us to estimate the probability of potential drug interactions with simultaneously administrated drugs that are metabolized by these CYP enzymes. In conclusion, the presence of adverse effects due to drug-drug interactions with concomitantly used drugs cannot be excluded, and hence, topical application may be recommended as a relatively safe approach.