CYP3A4 is mainly responsibile for the metabolism of a new vinca alkaloid, vinorelbine, in human liver microsomes.

The metabolism of vinorelbine, a new anticancer agent belonging to the vinca alkaloid family, was investigated in human liver microsomes. Vinorelbine biotransformation consisted of one saturable and one nonsaturable process, and the K(m) and V(max) values for the saturable process were 1.90 microM and 25.3 pmol/min/mg of protein, respectively. Several studies, including metabolism by cytochrome P450 (CYP) enzymes in a cDNA expression system and inhibition by specific antibodies and chemical inhibitors, showed that the main CYP enzyme involved in vinorelbine metabolism was CYP3A4. Also, the effects of vinorelbine on each of the CYP activities in human liver microsomes were investigated. High concentrations (100 microM) of vinorelbine inhibited CYP3A4 activity (testosterone 6beta-hydroxylation activity) by 45.2%. However, the inhibitory effects of vinorelbine on the other CYP activities were minimal. The 50% inhibitory concentration (IC(50)) of vinorelbine for testosterone 6beta-hydroxylase was estimated to be 155 microM. The plasma concentration in patients is expected to be much lower than this value. These results indicate that vinorelbine metabolism is expected to be modulated by the drugs that are able to inhibit or induce CYP3A activity.