Impact of the ultrarapid metabolizer genotype of cytochrome P450 2D6 on metoprolol pharmacokinetics and pharmacodynamics.
BACKGROUND
In the treatment of heart failure and hypertension with metoprolol, ultrarapid metabolizers (UMs) may not achieve optimal target concentrations with recommended doses. We compared metoprolol pharmacokinetics and effects in UMs with extensive metabolizers (EMs) and with poor metabolizers (PM) as an additional reference group.


METHODS
After a single dose of 100 mg metoprolol, pharmacokinetics, resting and exercise heart rate, and blood pressure were analyzed in relation to the CYP2D6 genotypes. We included 12 UMs, 13 EMs, and 4 PMs (healthy volunteers). CYP2D6 genotyping covered alleles *1 to *6 , *9 , *10 , *35 , and *41 and the duplications. beta 1 -Adrenergic receptor polymorphisms Ser49Gly and Arg389Gly were included as factors possibly interfering with the pharmacokinetic-pharmacodynamic relationship of metoprolol.


RESULTS
Median total metoprolol clearance values were 31, 168, and 367 L/h and median maximum plasma concentrations were 260, 118, and 67 microg/L in PMs, EMs, and UMs, respectively ( P < .0001). At 6 hours after administration, metoprolol reduced the exercise heart rate by median values of 31, 21, and 18 beats/min in PMs, EMs, and UMs, respectively ( P = .01). Blood pressure did not significantly differ according to CYP2D6 .


CONCLUSIONS
A linear relationship between the number of active CYP2D6 genes and metabolic clearance of metoprolol was found and the the median clearances differed by more than 10-fold between the PM and the UM groups. Metoprolol pharmacodynamics, however, differed only by less than 2-fold, and there was only a marginal difference in metoprolol efficacy on heart rate between the EM and UM groups.
Institute of Clinical Pharmacology, Humboldt University, Berlin, Germany. julia.kirchheiner@uk-koeln.de
Julia
J
Kirchheiner
Claudia
C
Heesch
Steffen
S
Bauer
Christian
C
Meisel
Angela
A
Seringer
Mark
M
Goldammer
Mladen
M
Tzvetkov
Ingolf
I
Meineke
Ivar
I
Roots
Jürgen
J
Brockmöller
D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D000483:Alleles; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005080:Exercise Test; D005260:Female; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol