Key result
Strong CYP2D6 inhibitors boost metoprolol exposure up to 8-fold, precipitating severe bradycardia and hypotension.
Why the study?
Metoprolol pharmacokinetics and pharmacodynamics vary significantly between individuals, partly from CYP2D6 polymorphisms, and co-administration of CYP2D6 inhibitors can induce phenoconversion with clinically significant changes in exposure and response.
Does the co-administration of CYP2D6 inhibitors alter metoprolol pharmacokinetics and pharmacodynamics based on CYP2D6 genotype?
Does the co-administration of CYP2D6 inhibitors alter metoprolol pharmacokinetics and pharmacodynamics based on CYP2D6 genotype?
Co-administration of CYP2D6 inhibitors with metoprolol causes clinically significant phenoconversion, markedly increasing drug exposure and the risk of adverse cardiovascular events like bradycardia and hypotension.
Alerts clinicians to metoprolol toxicity risk with CYP2D6 inhibitors; extends observational data but leaves open prospective validation.
Metoprolol, a β1-selective blocker, is widely used for treating cardiovascular and non-cardiovascular conditions. Its pharmacokinetics (PK) and pharmacodynamics (PD) vary significantly between individuals, in part due to CYP2D6 genetic polymorphisms. Co-administration of CYP2D6 inhibitors can lead to phenotype-genotype discordance, known as phenoconversion, resulting in clinically significant changes in metoprolol exposure and response. This review examines studies of the combined impact of CYP2D6 genotype and inhibitor use on metoprolol PK and PD. A literature search of PubMed, Embase, and Scopus identified 17 relevant clinical studies. Strong inhibitors such as paroxetine and fluoxetine increased metoprolol exposure by up to 8-fold and induced phenoconversion in extensive metabolizers. Moderate inhibitors, including mirabegron and amiodarone, increased metoprolol exposure by 2- to 3-fold, particularly in those with high baseline CYP2D6 activity. These inhibitors also reduced heart rate and blood pressure, mimicking the response seen in poor metabolizers. Weak inhibitors caused minimal PK changes without notable PD effects. Severe adverse drug reactions, including bradycardia and hypotension, occurred with strong inhibitors, especially in patients with cardiovascular disease and reduced CYP2D6 function. CYP2D6 phenoconversion is a clinically important but often overlooked contributor to metoprolol response variability. Incorporating phenoconversion into clinical practice can lead to more effective pharmacotherapy with metoprolol.
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Azizi et al. (2025) conducted a review in Metoprolol response variability (n=17). CYP2D6 inhibitors was evaluated on Metoprolol exposure and pharmacodynamic response. Co-administration of strong CYP2D6 inhibitors increased metoprolol exposure by up to 8-fold and induced phenoconversion, leading to severe adverse reactions like bradycardia and hypotension.
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