Impact of CYP2D6*10 on mexiletine pharmacokinetics in healthy adult volunteers.
OBJECTIVE
In vitro studies with human liver microsomes have suggested that the oxidative conversion of mexiletine (MX) to its metabolites is catalyzed by CYP2D6 and is significantly impaired in microsomes with the CYP2D6*10/*10 genotype. Therefore, we examined the influence of the CYP2D6*10 allele on MX pharmacokinetics in Japanese subjects.


METHODS
Subjects with CYP2D6*1/*1 (group *1/*1; n=5), CYP2D6*10/*10 (group *10/*10; n=6) and CYP2D6*5/*10 (group *5/*10; n=4) genotypes received a single 200-mg dose of MX. Plasma and urinary levels of MX and its metabolites ( p-hydroxymexiletine (PHM), hydroxymethylmexiletine (HMM) and N-hydroxymexiletine (NHM)) were determined by means of high-performance liquid chromatography.


RESULTS
Mean area under the concentration-time curve (AUC) and t(1/2) of MX were significantly ( P<0.05) higher in the CYP2D6*10/*5 group (AUC 11.23+/-3.05 micro g.h/ml; t(1/2) 15.5+/-3.2 h) than in the CYP2D6*1/*1 (AUC 5.53+/-1.01 micro g.h/ml; t(1/2) 8.1+/-1.6 h) and CYP2D6*10/*10 (AUC 7.32+/-2.36 micro g.h/ml; t(1/2) 10.8+/-2.8 h) groups, but there was no significant difference between the CYP2D6*1/*1 and CYP2D6*10/*10 groups. The maximum plasma concentration of MX was not significantly different among the three groups. The values of urinary excretion of PHM and HMM in the CYP2D6*1/*1 group were significantly ( P<0.05) higher than those in the CYP2D6*10/*10 and CYP2D6*5/*10 groups, but there was no significant difference in that of NHM among the three groups. Clearance of MX in the CYP2D6*5/*10 subjects was comparable to that in the poor metabolizers described previously.


CONCLUSIONS
The present findings demonstrated that carriers of the CYP2D6*10 allele showed a decreased clearance of MX. Subjects with CYP2D6*5/ *10 showed significantly ( P<0.05) increased plasma levels of MX, and homozygotes for CYP2D6*10 also showed an increase, although to a lesser extent. Thus, the CYP2D6*10 allele plays an important role in MX pharmacokinetics.
Otani
Masahiro
M
Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Japan.
Fukuda
Tsuyoshi
T
Naohara
Masakazu
M
Maune
Hiromi
H
Senda
Chiaki
C
Yamamoto
Isamu
I
Azuma
Junichi
J
D000284:Administration, Oral; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007564:Japan; D016014:Linear Models; D008297:Male; D008801:Mexiletine / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000889:Anti-Arrhythmia Agents; D008801:Mexiletine; D019389:Cytochrome P-450 CYP2D6