Nonlinear mixed effects model analysis of the pharmacokinetics of routinely administered bepridil in Japanese patients with arrhythmias.
This study was performed to evaluate variability in the pharmacokinetics of bepridil in 38 Japanese patients with arrhythmias, and to investigate the effects of aprindine as well as CYP2D6 and CYP3A5 polymorphisms on the oral clearance of bepridil. We determined the polymorphic alleles of CYP2D6 and CYP3A5 in each subject. The plasma concentration of bepridil at steady-state following repetitive oral administration was measured with an HPLC-based method, and the oral clearance was estimated using the nonlinear mixed effects model (NONMEM) program. Mean oral clearance was significantly greater in the patients with the CYP2D6*10 allele than in those without it. On the other hand, no significant effect of the CYP3A5 polymorphism was observed on the pharmacokinetics of bepridil. In addition, aprindine seemed to reduce the oral clearance of bepridil in the patients with the CYP2D6*10 allele.
Taguchi
Masato
M
Graduate School of Pharmaceutical Sciences, University of Toyama, Sugitani, Japan.
Fujiki
Akira
A
Iwamoto
Jotaro
J
Inoue
Hiroshi
H
Tahara
Katsutoshi
K
Saigusa
Katsuya
K
Horiuchi
Isao
I
Oshima
Yukari
Y
Hashimoto
Yukiya
Y
D000328:Adult; D000368:Aged; D000465:Algorithms; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001073:Aprindine / Q000493:pharmacokinetics / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000378:metabolism*; D015764:Bepridil / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D003627:Data Interpretation, Statistical; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D017711:Nonlinear Dynamics
D000889:Anti-Arrhythmia Agents; D001073:Aprindine; D015764:Bepridil; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A