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

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.