Influence of CYP2D6 genotype on metoprolol plasma concentration and beta-adrenergic inhibition during long-term treatment: a comparison with bisoprolol.
In patients routinely treated with metoprolol, influences of CYP2D6 genotype on the response of heart rate to isoproterenol (IP) were studied at its peak and trough concentrations and were compared with those of bisoprolol. In 72 patients treated with metoprolol or bisoprolol, CYP2D6 genotype (ie, CYP2D6*1, *2, *4, *5, *10, and *14) was determined. No patients except one who was heterozygous for CYP2D6*5 carried the null alleles of CYP2D6. The homozygote frequency for CYP2D6*10 was relatively high (19.4%) and these patients had greater peak and trough plasma concentrations of metoprolol than the other patients. Isoproterenol-induced percentage increases in heart rate were 58% and 38% less at the low and high rate of isoproterenol infusion (0.02 and 0.04 microg/kg/min), respectively, in patients homozygous for CYP2D6*10 than in the other patients at the trough, but not at the peak concentrations. In contrast, CYP2D6 genotype did not affect plasma concentrations of bisoprolol and the extent of its beta-adrenergic inhibition. Thus, in patients routinely treated with metoprolol, CYP2D6 genotype significantly affects circadian variations of beta-adrenergic inhibition induced by metoprolol. In contrast, bisoprolol has a relatively constant beta-adrenergic inhibition independent of CYP2D6 genotype.
Nozawa
Takashi
T
Second Department of Internal Medicine, Toyama Medical & Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. tnozawa@ms.toyama-mpu.ac.jp
Taguchi
Masato
M
Tahara
Katsutoshi
K
Hashimoto
Yukiya
Y
Igarashi
Norio
N
Nonomura
Makoto
M
Kato
Bun-ichi
B
Igawa
Akihiko
A
Inoue
Hiroshi
H
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D000368:Aged; D000483:Alleles; D017298:Bisoprolol / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000188:drug therapy; D002851:Chromatography, High Pressure Liquid; D002940:Circadian Rhythm; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004247:DNA / Q000235:genetics; D004334:Drug Administration Schedule; D005260:Female; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008790:Metoprolol / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013997:Time Factors
D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D004247:DNA; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol; D017298:Bisoprolol