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.
Jin
S K
SK
Department of Pharmacological Research, National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul, South Korea.
Chung
H J
HJ
Chung
M W
MW
Kim
J-I
JI
Kang
J-H
JH
Woo
S W
SW
Bang
S
S
Lee
S H
SH
Lee
H J
HJ
Roh
J
J
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