title: Amiodarone N-deethylation by CYP2C8 and its variants, CYP2C8*3 and CYP2C8 P404A.
abstract: 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.
authors.affiliation: Project Team for Pharmacogenetics, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Soyama
authors.forename: Nobumitsu
authors.initials: N
authors.lastname: Hanioka
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Norie
authors.initials: N
authors.lastname: Murayama
authors.forename: Masanori
authors.initials: M
authors.lastname: Ando
authors.forename: Shogo
authors.initials: S
authors.lastname: Ozawa
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sawada
mesh_terms: D000638:Amiodarone / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000494:pharmacology*; D065727:Cytochrome P-450 CYP2C8; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D017239:Paclitaxel / Q000378:metabolism* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; C036116:desethylamiodarone; D000638:Amiodarone; D017239:Paclitaxel