Effect of the CYP2D6*10 genotype on venlafaxine pharmacokinetics in healthy adult volunteers

被引:78
作者
Fukuda, T
Yamamoto, I
Nishida, Y
Zhou, Q
Ohno, M
Takada, K
Azuma, J
机构
[1] Osaka Univ, Grad Sch Pharmaceut Sci, Suita, Osaka 565, Japan
[2] Kyoto Pharmaceut Univ, Dept Pharmacokinet, Kyoto 607, Japan
关键词
CYP2D6*10 genotype; pharmacokinetics; venlafaxine;
D O I
10.1046/j.1365-2125.1999.00913.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Aims Interindividual differences in the pharmacokinetics of venlafaxine, a new antidepressant, were shown during early clinical trials in Japan. Venlafaxine is metabolized mainly by CYP2D6 to an active metabolite, O-desmethylvenlafaxine (ODV). Therefore, the influence of the CYP2D6 genotypes on venlafaxine pharmacokinetics was examined in a Japanese population. Methods Twelve adult Japanese men in good health participated in this study. Genomic DNA was isolated from peripheral lymphocytes, and the CYP2D6 genotypes were determined by codon 188C/T, 1934G/A, 2938G/A and 4268G/C mutations using endonuclease tests based on PCR and by Xba I-RFLP analysis. Subjects were categorized into the following 3 groups (n = 4 in each group); Group1: CYP2D6(star)10/(star)10, (star)5/(star)10, Group2: CYP2D6(star)1/(star)10, (star)2/(star)10 and Group3: CYP2D6(star)1/(star)1, CYP2D6(star)1/(star)2. Venlafaxine (25 mg, n=6; 37.5 mg, n=6) was administered orally at 09.00 h following an overnight fast. Plasma concentrations of venlafaxine and ODV were monitored by h.p.l.c. for 48 h. Results The C-max and AUC of venlafaxine were 184% and 484% higher in the group 1 subjects than in the group 3 subjects, and 101% and 203% higher in the group 1 than in the group 2, respectively. Conclusions These results suggest that CYP2D6(star)10 influences the pharmacokinetics of venlafaxine in a Japanese population.
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收藏
页码:450 / 453
页数:4
相关论文
共 17 条
[1]   THE CYTOCHROME-P450 CYP2D6 ALLELIC VARIANT CYP2D6J AND RELATED POLYMORPHISMS IN A EUROPEAN POPULATION [J].
ARMSTRONG, M ;
FAIRBROTHER, K ;
IDLE, JR ;
DALY, AK .
PHARMACOGENETICS, 1994, 4 (02) :73-81
[2]   DEBRISOQUINE SPARTEINE HYDROXYLATION GENOTYPE AND PHENOTYPE - ANALYSIS OF COMMON MUTATIONS AND ALLELES OF CYP2D6 IN A EUROPEAN POPULATION [J].
BROLY, F ;
GAEDIGK, A ;
HEIM, M ;
EICHELBAUM, M ;
MORIKE, K ;
MEYER, UA .
DNA AND CELL BIOLOGY, 1991, 10 (08) :545-558
[3]   GENETIC-ANALYSIS OF THE CYP2D LOCUS IN RELATION TO DEBRISOQUINE HYDROXYLATION CAPACITY IN KOREAN, JAPANESE AND CHINESE SUBJECTS [J].
DAHL, ML ;
YUE, QY ;
ROH, HK ;
JOHANSSON, I ;
SAWE, J ;
SJOQVIST, F ;
BERTILSSON, L .
PHARMACOGENETICS, 1995, 5 (03) :159-164
[4]   Nomenclature for human CYP2D6 alleles [J].
Daly, AK ;
Brockmoller, J ;
Broly, F ;
Eichelbaum, M ;
Evans, WE ;
Gonzalez, FJ ;
Huang, JD ;
Idle, JR ;
IngelmanSundberg, M ;
Ishizaki, T ;
JacqzAigrain, E ;
Meyer, UA ;
Nebert, DW ;
Steen, VM ;
Wolf, CR ;
Zanger, UM .
PHARMACOGENETICS, 1996, 6 (03) :193-201
[5]   VENLAFAXINE - A HETEROCYCLIC ANTIDEPRESSANT [J].
ELLINGROD, VL ;
PERRY, PJ .
AMERICAN JOURNAL OF HOSPITAL PHARMACY, 1994, 51 (24) :3033-3046
[6]   GENOTYPING OF POOR METABOLIZERS OF DEBRISOQUINE BY ALLELE-SPECIFIC PCR AMPLIFICATION [J].
HEIM, M ;
MEYER, UA .
LANCET, 1990, 336 (8714) :529-532
[7]   METOPROLOL AND MEPHENYTOIN OXIDATION POLYMORPHISMS IN FAR EASTERN ORIENTAL SUBJECTS - JAPANESE VERSUS MAINLAND CHINESE [J].
HORAI, Y ;
NAKANO, M ;
ISHIZAKI, T ;
ISHIKAWA, K ;
ZHOU, HH ;
ZHOU, BJ ;
LIAO, CL ;
ZHANG, LM .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1989, 46 (02) :198-207
[8]   METABOLIC DISPOSITION OF C-14 VENLAFAXINE IN MOUSE, RAT, DOG, RHESUS-MONKEY AND MAN [J].
HOWELL, SR ;
HUSBANDS, GEM ;
SCATINA, JA ;
SISENWINE, SF .
XENOBIOTICA, 1993, 23 (04) :349-359
[9]  
JOHANSSON I, 1994, MOL PHARMACOL, V46, P452
[10]   PROPRANOLOL DISPOSITION IN CHINESE SUBJECTS OF DIFFERENT CYP2D6 GENOTYPES [J].
LAI, ML ;
WANG, SL ;
LAI, MD ;
LIN, ET ;
TSE, M ;
HUANG, JD .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1995, 58 (03) :264-268