Abstract:
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. CONCLUSION: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.
journal_name
Eur J Clin Pharmacoljournal_title
European journal of clinical pharmacologyauthors
Otani M,Fukuda T,Naohara M,Maune H,Senda C,Yamamoto I,Azuma Jdoi
10.1007/s00228-003-0656-5subject
Has Abstractpub_date
2003-09-01 00:00:00pages
395-9issue
5-6eissn
0031-6970issn
1432-1041journal_volume
59pub_type
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journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
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abstract::All forensic autopsy cases in southern Sweden in 1986-89 in which antidepressant drugs were found in the blood were assessed and the findings related to the sales of antidepressants as expressed as defined daily doses per 1,000 inhabitants per day. There was a total of 272 antidepressant-positive cases, which were div...
journal_title:European journal of clinical pharmacology
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journal_title:European journal of clinical pharmacology
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