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

References: 

1. Regardh CG, Johnsson G.  Clinical pharmacokinetics of metoprolol.  Clin Pharmacokinet  1980;5:557-69.
   
2. Lennard MS, Silas JH, Freestone S et al.  Oxidation phenotype - a major determined of metoprolol metabolism and response.  N Eng J Med 1982;307:1558-1560.
3. 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.
4. 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 1993;90:11825-11829.
5. 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.
6. 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  2008;64:883-8.
7. Fox K, Borer JS, Camm AJ et al.  Resting heart rate in cardiovascular disease.  J Am Coll Cardiol  2007;50:823-30.

• Pharmacogenetics:  CYP2D6 Genetic Polymorphisms Reference Table
  
• Drug Monograph:  Carvedilol (Coreg)
  

metoprolol, beta blocker, beta receptor antagonist, CYP2D6, 2D6, ultra rapid metabolizer, pulse, heart rate