Antitumor platinum complexes based on transplatin inhibit human liver microsomal cytochromes P450

Nine forms of human mirosomal hepatic cytochromes P450 (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4) with platinum complexes wasstudied. Compounds used in this study were cisplatin, oxaliplatin, carboplatin, transplatin and two transplatin derivatives with alkylamine ligands. Carboplatin did not inhibit the activities; with cisplatin and oxaliplatin, a minor inhibition of CYP2C9 enzyme was seen; cisplatin also inhibited slightly the CYP2B6 activity. As the plasmatic levels of cisplatin obtained in clinical applications are low the effects are most probably not important. On the other hand, transpla­tin, a clinically ineffective compound, inhibited the CYP2B6 as well as CYP2C9 activities significantly; also, an inhibition of CYP2E1 activity was found with this form of platinum complex. Two new complexes based on the structure of transplatin inhibited CYP activities more strongly reaching nearly a complete inhibition of the respective CYP activities. The IC50 values were found to be below 100 µM indicating that there is a possibility of potential interactions of these transplatin derivatives with drugs metabolized by CYP3A4, CYP2E1, CYP2D6, CYP2C19, CYP2B6, CYP2A6 and CYP1A2 enzymes. Clinically nonsignificant inhibition was found with the CYP2C9 and CYP2C8. This fact indicates a low probability of interactions with drugs metabolized by these CYP enzymes, namely with warfarin, nonsteroid antiinflamatory agents (as e.g. profenes) or oral hypoglycemics. Hence, the interactions with drug metabolizing human liver microsomal cytochromes P450 with new antitumor agents based on the transplatin cannot be ruled out.