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

Drug Metab Dispos. 2000 Sep;28(9):1121-7.


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.

MeSH terms

  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / drug effects
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydroxylation / drug effects
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Kinetics
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism*
  • Mixed Function Oxygenases / drug effects
  • Mixed Function Oxygenases / genetics
  • Mixed Function Oxygenases / metabolism*
  • Recombinant Proteins / metabolism
  • Steroid Hydroxylases / drug effects
  • Steroid Hydroxylases / metabolism
  • Substrate Specificity
  • Testosterone / metabolism
  • Vinblastine / analogs & derivatives*
  • Vinblastine / pharmacokinetics
  • Vinblastine / pharmacology
  • Vinca Alkaloids / pharmacokinetics*
  • Vinca Alkaloids / pharmacology
  • Vinorelbine


  • Enzyme Inhibitors
  • Isoenzymes
  • Recombinant Proteins
  • Vinca Alkaloids
  • Testosterone
  • Vinblastine
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Steroid Hydroxylases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • steroid hormone 6-beta-hydroxylase
  • CYP3A4 protein, human
  • Vinorelbine