Enantiospecific pharmacokinetics of metoprolol in CYP2D6 ultra-rapid metabolizers and correlation with exercise-induced heart rate.
OBJECTIVE
Our objective was to study the enantioselective pharmacokinetics of metoprolol in CYP2D6 ultra-rapid metabolizers (UM) compared with extensive (EM) and poor (PM) metabolizers to quantify differential effects of metoprolol enantiomers on the beta1-adrenoreceptor blockade.


METHODS
Twenty-nine healthy individuals were selected based on their CYP2D6 genotype, and 100 mg racemic metoprolol was administered. Plasma concentrations of R- and S-metoprolol and the metabolites SS-, SR-, RS-, and RR-hydroxymetoprolol were quantified by high-performance liquid chromatography.


RESULTS
Mean (+/-SD) AUCs of S-metoprolol were 190 +/- 99 ng/ml x h in UMs, 366 +/- 158 in EMs, and 1,804 +/- 300 in PMs. For R-metoprolol, the AUCs were 127 +/- 72 ng/ml x h in UMs, 261 +/- 126 in EMs, and 1,746 +/- 319 in PMs. The concentrations of R-metoprolol and S-metoprolol, respectively, needed to obtain a half-maximum reduction in heart rate were estimated as 20 and 21 ng/ml in PMs, 11 and 17 ng/ml in EMs, and 7 and 11 ng/ml in UMs.


CONCLUSIONS
A slight enantiopreference towards metabolism of R-metoprolol by CYP2D6 was observed in EMs and even more in the UM group, but the effect was far from being enantioselective.
Institute of Pharmacology of Natural Products & Clinical Pharmacology, University of Ulm, Ulm, Germany. angela.seeringer@uni-ulm.de
Angela
A
Seeringer
Jürgen
J
Brockmöller
Steffen
S
Bauer
Julia
J
Kirchheiner
D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D019540:Area Under Curve; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D015444:Exercise; D005080:Exercise Test; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008790:Metoprolol / Q000493:pharmacokinetics*; D010597:Pharmacogenetics; D018709:Statistics, Nonparametric; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol