Pharmacogenetics of Beta-Blockers

Jaekyu Shin, Pharm.D.; Julie A. Johnson, Pharm.D.


Pharmacotherapy. 2007;27(6):874-887. 

In This Article

β-Blocker Responses and CYP2D6 Gene Polymorphism

Differences in drug metabolism can cause variability in pharmacokinetics, which may produce variable responses. Many of the β-blockers are substrates for the cytochrome P450 (CYP) 2D6 enzyme, including metoprolol, carvedilol, propranolol, labetalol, and timolol.[52] Among the β-blockers, metoprolol is most highly dependent on the CYP2D6 enzyme, with 70-80% of its metabolism through this pathway. The CYP2D6 gene is highly polymorphic with about 80 alleles reported.[53] Patients are commonly classified as ultraextensive metabolizers, extensive metabolizers, intermediate metabolizers, or poor metabolizers based on the number of copies of functional CYP2D6 alleles. The well-known influence of CYP2D6 genotype on metoprolol pharmacokinetics[54,55,56] has led to obvious ques-tions about the effect of these kinetic differences on adverse effects or efficacy. These studies are summarized in Table 8 ,[34,57–59] which highlights that despite the dramatic effects of CYP2D6 genotype on pharmacokinetics, this does not appear to translate into differences in efficacy or adverse effects.

In a case-control study, adverse events associated with metoprolol therapy were 4.9–5.2-fold more likely to occur in poor metabolizers than in non–poor metabolizers (p<0.0001).[57] However, it was a retrospective study with a small sample size. Prospective studies with larger samples did not confirm these results. Specifically, although the expected effects of CYP2D6 genotype on pharmacokinetics of metoprolol were observed, rates of efficacy or adverse effects were not significantly different between the poor metabolizer and non–poor metabolizer groups.[34,58,59] This was perhaps most surprising in patients with heart failure, in whom therapy must be started at very low doses (concentrations). However, even in this population, CYP2D6 genotype was not associated with poor tolerability to metoprolol CR/XL on initiation of therapy.[32] Although no studies have compared adverse-event rate or efficacy of metoprolol between ultraextensive and extensive metabolizers, it is unlikely that there would be differences in the adverse-event rate between the two groups. It is possible that ultraextensive metabolizers would require higher doses to achieve β-blockade, but this would be easy to detect and address clinically (without genotyping) since resting heart rate is a sensitive marker for the degree of β-blockade.

Thus, the studies suggest CYP2D6 genotype influences neither efficacy nor toxicity with metoprolol. Since the other β-blockers are much less reliant on CYP2D6 than metoprolol, it is also likely that their efficacy and toxicity will not be significantly influenced by CYP2D6 genotype. Thus, despite the clinical availability of CYP2D6 genotyping, data suggest such genotyping would be of little clinical benefit.


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