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 CYP2D610 allele on MX pharmacokinetics in Japanese subjects.

METHODS

Subjects with CYP2D6*1/*1 (group *1/1; n=5), CYP2D610/*10 (group *10/10; n=6) and CYP2D65/*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 CYP2D61/1 (AUC 5.53+/-1.01 micro g.h/ml; t(1/2) 8.1+/-1.6 h) and CYP2D610/10 (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 CYP2D61/1 and CYP2D610/10 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 CYP2D61/1 group were significantly ( P<0.05) higher than those in the CYP2D610/10 and CYP2D65/10 groups, but there was no significant difference in that of NHM among the three groups. Clearance of MX in the CYP2D65/*10 subjects was comparable to that in the poor metabolizers described previously.

CONCLUSION

The present findings demonstrated that carriers of the CYP2D610 allele showed a decreased clearance of MX. Subjects with CYP2D65/ 10 showed significantly ( P<0.05) increased plasma levels of MX, and homozygotes for CYP2D610 also showed an increase, although to a lesser extent. Thus, the CYP2D6*10 allele plays an important role in MX pharmacokinetics.