Amiodarone N-deethylation by CYP2C8 and its variants, CYP2C8*3 and CYP2C8 P404A

Pharmacol Toxicol. 2002 Oct;91(4):174-8. doi: 10.1034/j.1600-0773.2002.910404.x.


Amiodarone is a potent Class III antiarrhythmic drug. The N-deethylation of amiodarone to desethylamiodarone is known to be catalyzed by cytochrome P450 (CYP) 2C8. In the present study, amiodarone N-deethylation by the CYP2C8s, CYP2C8*1 (wild-type), CYP2C8*3, and CYP2C8 P404A (Pro404Ala substitution in exon 8), was investigated by their transient expression in Hep G2 cells. The expression levels of CYP2C8*1 and CYP2C8*3 were similar, whereas the level of CYP2C8 P404A was 55.6% of that of CYP2C8*1. The kinetic parameters of amiodarone N-deethylation were obtained by means of Lineweaver-Burk analysis. The intrinsic clearance (Vmax/Km, per mg of microsomal protein) of amiodarone by CYP2C8 P404A but not CYP2C8*3 was significantly (48.7%) less than that of CYP2C8*1. These results suggest that CYP2C8 P404A but not CYP2C8*3 is less effective in the N-deethylation of amiodarone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amiodarone / analogs & derivatives*
  • Amiodarone / metabolism*
  • Amiodarone / pharmacokinetics
  • Aryl Hydrocarbon Hydroxylases / pharmacology*
  • Cytochrome P-450 CYP2C8
  • Metabolic Clearance Rate
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology*
  • Microsomes, Liver / metabolism
  • Paclitaxel / metabolism*
  • Paclitaxel / pharmacokinetics
  • Structure-Activity Relationship
  • Transfection


  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • desethylamiodarone
  • Amiodarone
  • Paclitaxel