Influence of CYP2D6*10 on the pharmacokinetics of metoprolol in healthy Korean volunteers.
OBJECTIVE
Genetic polymorphism of CYP2D6 leads to differences in pharmacokinetics of CYP2D6 substrates. The CYP2D6*10 allele is clinically important in Koreans because of its high frequency in Asians. We investigated whether the pharmacokinetics of metoprolol was altered by the presence of the CYP2D6*10 allele in Korean subjects.


METHODS
One hundred and seven volunteers were recruited and grouped as CYP2D6*1/*1, CYP2D6*1/*10 and CYP2D6*10/*10 according to their genotypes. Metoprolol tartrate 100 mg (Betaloc) was administered orally once to each subject in these three groups (n = 6, 7 and 5, respectively). The pharmacokinetic parameters of metoprolol and its metabolite, alpha-hydroxymetoprolol, and the metabolic ratio for the three groups were estimated and compared.


CONCLUSIONS
The area under the plasma concentration-time curve (AUC(0-->infinity)), the maximum plasma concentration (C(max)) and the elimination half-life (T(1/2)) of metoprolol and alpha-hydroxymetoprolol for the CYP2D6*10/*10 group were all significantly different from those of the CYP2D6*1/*1 group (P < 0.05). The AUC(0-->infinity)s of metoprolol were 443.7 +/- 168.1, 995.6 +/- 321.4 and 2545.3 +/- 632.0 ng.h/mL, and the AUC(0-->infinity)s of alpha-hydroxymetoprolol were 1232.0 +/- 311.2, 1344.0 +/- 288.1 and 877.4 +/- 103.4 ng.h/mL for groups CYP2D6*1/*1, *1/*10 and *10/*10, respectively. The corresponding T(1/2) values of metoprolol were 2.7 +/- 0.5, 3.2 +/- 1.3 and 5.0 +/- 1.1 h, while those of alpha-hydroxymetoprolol were 5.4+/-1.5, 6.0 +/- 1.4 and 10.5 +/- 4.2 h, respectively. The metabolic ratios of the three groups were significantly different (P < 0.05).


CONCLUSIONS
The CYP2D6*10 allele altered the pharmacokinetics of metoprolol in Korean subjects and is likely to affect other drugs metabolized by the CYP2D6 enzyme, similarly.
Department of Pharmacological Research, National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul, South Korea.
S K
SK
Jin
H J
HJ
Chung
M W
MW
Chung
J-I
JI
Kim
J-H
JH
Kang
S W
SW
Woo
S
S
Bang
S H
SH
Lee
H J
HJ
Lee
J
J
Roh
D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D000328:Adult; D000483:Alleles; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006207:Half-Life; D006801:Humans; D007723:Korea; D008297:Male; D008790:Metoprolol / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D055815:Young Adult
D000319:Adrenergic beta-Antagonists; C029504:alpha-hydroxymetoprolol; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol