Metoprolol (Lopressor) is a well-known beta-1 selective beta-blocker used
most commonly for hypertension, rate control, and heart failure. In
relation to its pharmacokinetic profile, metoprolol is the most dependent on
CYP2D6 enzyme for its metabolism. In fact, it is known that about 70-80%
of metoprolol's metabolism is dependent on this phase 1 metabolic pathway.1-3
Unfortunately, CYP2D6 is subject to genetic polymorphisms which can change its
efficiency in metabolizing medication substrates of CYP 2D6. Patient can
be categorized as ultra-rapid metabolizers (UM), extensive metabolizers (EM),
or poor metabolizers (PM). The normal type in the general population are
EM. Ultra-rapid metabolizers have the genetic polymorphism CYP2D6*2xn and
are known to more efficiently metabolize medications like metoprolol more
efficiently.4-6 This means that the plasma concentrations of metoprolol
will be less that what might be expected with normal doses and frequency of
administration.5,6 As such, this could compromise the desired therapeutic
benefits of metoprolol in patients with cardiovascular disease who need
adequate reductions in heart rate.
The influence of being a UM and the ability of metoprolol to reduce the
heart rate was assessed by a single dose pharmacokinetic and pharmacodynamic
study.5 This study confirmed that the concentrations of metoprolol were
not only lower, but that metoprolol was less effective at reducing the exercise
induced heart rate compared to patients known to either be EM or PM. The
single 100 mg dose of metoprolol reduced the exercise heart rate by a median of
31 beats per minute (bpm) for PMs, 21 bpm for EM, and only 18 bpm for UM.
While the margin of difference between UM and EM was not clinically
significant, it may help to explain why some patients will have different
pharmacodynamic effects despite using similar doses. The CYP2D6 may be
one of several contributing factors that may explain why some patients may not
obtain the desired reductions in pulse as might be desired or expected.
This is clinically relevant since it well known that reductions in the pulse to
target ranges is known to reduce cardiovascular related mortality.7
- Regardh CG, Johnsson G. Clinical pharmacokinetics of metoprolol. Clin Pharmacokinet 1980;5:557-69.
- Lennard MS, Silas JH, Freestone S et al. Oxidation phenotype - a
major determined of metoprolol metabolism and response. N Eng J Med
- Lennard MS, Tucker GT, Silas JH et al. Debrisoquine polymorphism
and the metabolism and action of metoprolol, timolol, propranolol and
atenolol. Xenobiotica 1986;16:435-447.
- Johansson I, Lundqvist E, Bertilsson L et al. Inherited
amplification of an active gene in the cytochrome P450 CYP2D locus as a
cause of ultrarapid metabolism of debrisoquine. Proc Nat Acad Sci
- Kirchheiner J et al. Impact of the ultrarapid metabolizer
genotype of cytochrome P450 2D6 on metoprolol pharmacokinetics and
pharmacodynamics. Clin Pharmacol Ther 2004;76:302-312.
- Seeringer A, Brockmoller J, Bauer S et al. Enantiospecific
pharmacokinetics of metoprolol in CYP2D6 ultra-rapid metabolizers and
correlation with exercise-induced heart rate. Eur J Clin Pharmacol
- Fox K, Borer JS, Camm AJ et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol 2007;50:823-30.