Metoprolol and CYP2D6: A Retrospective Cohort Study Evaluating Genotype-Based Outcomes

Abstract

Metoprolol is a medication commonly utilized in select patients to achieve a reduction in heart rate, systolic blood pressure, or other indications. A majority of metoprolol metabolism occurs via CYP2D6. Decreased expression of the CYP2D6 enzyme increases the concentration of metoprolol. Current pharmacogenomics guidelines by the Dutch Pharmacogenomics Working Group recommend slower titrations and dose decreases to minimize adverse effects from poor metabolizers or normal metabolizers taking concomitant medications that are strong inhibitors of CYP2D6 (phenoconverters). This study aimed to evaluate adverse effects such as bradycardia, hypotension, and syncope in patients who are expected to have absent CYP2D6 enzyme activity due to drug–drug or drug–gene interactions. The secondary aims of this study were to evaluate heart rate measurements for the included participants. Retrospective data were collected for individuals with CYP2D6 genotyping results obtained for clinical purposes. Three categories (CYP2D6 normal metabolizers, poor metabolizers, and phenoconverters) were assigned. A total of 325 participants were included. There was no statistically significant difference found in the primary composite outcome between the three metabolizer groups (p = 0.054). However, a statistically significant difference was identified in the incidences of bradycardia between the poor metabolizers and the normal metabolizers or phenoconverters (p < 0.0001). The average heart rates were 2.8 beats per minute (bpm) and 2.6 bpm lower for the poor metabolizer and phenoconverter groups, respectively, compared to the normal metabolizers (p < 0.0001 for both comparisons). This study further supports the role of genetic testing in precision medicine to help individualize patient care as CYP2D6 poor metabolizers taking metoprolol were found to have an increase in bradycardia. Additional research is needed to clarify the dose relationship in this drug–gene interaction.

Precision medicine in cardiovascular therapeutics: Evaluating the role of pharmacogenetic analysis prior to drug treatment

“…The CYP2D6 genotype influences the pharmacokinetics of all these drugs. However, it is noteworthy that these pharmacokinetic variations predominantly manifest as differences in heart rate, as opposed to other response phenotypes such as hypertension [32,33]. Various studies -including those by Thomas and Johnson [30] and Cunningham and Chapman [34] -have underscored this distinction.…”

Pediatric Beta Blocker Therapy: A Comprehensive Review of Development and Genetic Variation to Guide Precision-Based Therapy in Children, Adolescents, and Young Adults

“…This was validated in a systematic review and meta analysis by Blake et al [ 108 ]. These pharmacogenetic observations may have clinical relevance leading to adverse events (e.g., bradycardia), where those with poor metabolism genotypes have a significantly higher bradycardia event rate relative to those with normal metabolism genotypes [ 109 , 110 ]. Despite CYP2D6 contributing to the majority of metoprolol biotransformation, metoprolol did have a notable stereoselective effect.…”

Structure–activity relationships and interindividual variability of drug responses: pharmacogenomics with antimicrobial drugs as a paradigm

“…CYP2D6 poor metabolizers have a higher risk of bradycardia because of their higher levels of metoprolol. 57 Haloperidol is also metabolized by CYP2D6. A study by Brockm€ oller and colleagues reported that the risk of pseudoparkinsonism was higher in poor metabolizers.…”