Influence of the CYP2D6*10 allele on the metabolism of mexiletine by human liver microsomes.
OBJECTIVE
To study the influence of CYP2D6*10 on the formation of p-hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM) using microsomes from human liver of known genotypes.


METHODS
Microsomes from human livers of genotype CYP2D6*1/*1 (n = 5), *1/*10 (n = 6) and *10/*10 (n = 6) were used in this study. The formation of PHM and HMM was determined by high-performance liquid chromatography.


RESULTS
The formation rates of PHM and HMM were decreased by more than 50% and 85% in CYP2D6*1/*10 and *10/*10 microsomes, respectively, compared with *1/*1 microsomes.


CONCLUSIONS
The metabolism of mexiletine to form PHM and HMM appears to be impaired to a significant extent in human liver microsomes from hetero- and homozygotes of CYP2D6*10.
Senda
C
C
Department of Drug Metabolism and Pharmacokinetics, Kawanishi Pharma Research Institute, Nippon Boehringer Ingelheim Co, Hyogo.
Yamaura
Y
Y
Kobayashi
K
K
Fujii
H
H
Minami
H
H
Sasaki
Y
Y
Igarashi
T
T
Chiba
K
K
D000483:Alleles; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006900:Hydroxylation; D008801:Mexiletine / Q000493:pharmacokinetics*; D008862:Microsomes, Liver / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length
D000889:Anti-Arrhythmia Agents; D008801:Mexiletine; D019389:Cytochrome P-450 CYP2D6