Interaction of antitumor platinum complexes with human liver microsomal cytochromes P450.

Interaction of nine human hepatic cytochromes P450 (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) with six platinum complexes was studied using pooled human microsomes. The compounds used were cisplatin, oxaliplatin, carboplatin, transplatin, and trans-[PtCl2(NH3) (Am)], where Am=2-methylbutylamine or sec-butylamine. No significant inhibition of all CYP activities by carboplatin was observed. With cisplatin and oxaliplatin, a minor inhibition of CYP2C9 enzyme (75% of control at 400 miromol/l of these complexes) was seen; cisplatin also inhibited slightly the CYP2B6 activity (85% of control). With respect to plasma levels of cisplatin obtained in clinical applications, these effects are probably not important. In contrast, clinically ineffective transplatin, inhibited the CYP2B6 as well as CYP2C9 activities significantly (to 50-35% of control at 100 micromol/l); also, an inhibition of CYP2E1 activity was found here (to 70% at 100 micromol/l). Two other derivatives of transplatin (new antitumor agents with trans geometry), inhibited CYP activities more strongly reaching nearly a complete inhibition of the respective CYP activities at concentration of 200 micromol/l. Half maximal inhibitory concentration values were found in the range of tens of micromol/l indicating that there is a possibility of potential interactions of these compounds with drugs metabolized by CYP3A4, CYP2E1, CYP2D6, CYP2C19, CYP2B6, CYP2A6, and CYP1A2. Interestingly, clinically non-significant inhibition was found with the CYP2C9 and CYP2C8 indicating low probability of interactions with, for example, warfarin. The results document that the new antitumor agents based on the transplatin should be more thoroughly tested for interactions with liver microsomal drug-metabolizing cytochromes P450.