Metabolism of Metoprolol
Metoprolol is primarily metabolized by the CYP2D6 enzyme in the liver, with significant variability in metabolism based on genetic polymorphisms that can impact drug efficacy, safety, and dosing requirements. 1
Primary Metabolic Pathway
- Hepatic Metabolism: Metoprolol undergoes extensive first-pass metabolism in the liver with approximately 95% of the dose recoverable in urine 1
- CYP2D6 Dependency: The primary enzyme responsible for metoprolol metabolism is CYP2D6 1, 2
- Stereoselective Metabolism: Metoprolol is administered as a racemic mixture of R- and S-enantiomers with enantioselective metabolism that depends on oxidation phenotype 1
- Nearly 40% greater metabolism of R-metoprolol compared to S-metoprolol occurs in ultrarapid and extensive metabolizers 2
CYP2D6 Metabolizer Status Impact
Metoprolol metabolism varies significantly based on CYP2D6 metabolizer status:
Poor Metabolizers (PM):
- Approximately 8% of Caucasians and 2% of other populations 1
- Exhibit several-fold higher plasma concentrations of metoprolol 1
- Half-life extended to 7-9 hours (vs. 3-4 hours in extensive metabolizers) 1
- Up to 30-40% of oral or IV doses excreted unchanged in urine 1
- Experience greater heart rate reduction (2.8 bpm lower than normal metabolizers) 3
- Higher incidence of bradycardia compared to normal metabolizers 3
Extensive Metabolizers (EM):
Ultrarapid vs. Poor Metabolizers:
- 5.3-fold difference in peak plasma concentration
- 13-fold difference in area under the curve
- 2.6-fold difference in elimination half-life
- 15-fold difference in apparent oral clearance 2
Secondary Metabolic Pathways
While CYP2D6 is the primary metabolic pathway, other enzymes contribute to metoprolol metabolism:
- CYP3A4, CYP2B6, and CYP2C9: Collectively contribute approximately 4% to α-hydroxylation, 19% to O-demethylation, and 7.6% to N-dealkylation of metoprolol 4
- Induction Effects: Rifampicin can induce these secondary pathways, slightly affecting metoprolol metabolism, though not enough to compromise CYP2D6 phenotyping using metoprolol 4
Drug Interactions Affecting Metabolism
- CYP2D6 Inhibitors: Drugs that inhibit CYP2D6 (such as quinidine, fluoxetine, and tricyclic antidepressants) can increase metoprolol plasma concentrations 5
- Nicardipine: Produces a small increase in plasma metoprolol concentration in extensive metabolizers but not in poor metabolizers 6
- Hepatic Blood Flow: As a drug with high hepatic extraction ratio, metoprolol clearance depends primarily on hepatic blood flow, which decreases with age 5
Clinical Implications
- Dose Adjustments: May be required in poor metabolizers or when co-administered with CYP2D6 inhibitors to minimize adverse effects 5, 3
- Age-Related Changes: Decreased hepatic blood flow in older adults may require dose adjustments 5
- Hepatic Impairment: Elimination half-life is considerably prolonged (up to 7.2 hours) depending on severity of impairment 1
- Sex Differences: Women may experience higher exposure to CYP2D6-dependent β-blockers like metoprolol due to lower volume of distribution and reduced metabolism 5
- Pharmacodynamic Effects: Despite significant pharmacokinetic differences, blood pressure response and adverse effect rates (except bradycardia) do not differ significantly by CYP2D6 phenotype 7
Monitoring Considerations
- Heart Rate: More closely monitor heart rate in poor metabolizers or patients taking CYP2D6 inhibitors due to increased risk of bradycardia 3
- Elderly Patients: May show slightly higher plasma concentrations due to decreased metabolism and hepatic blood flow 1
- Renal Function: No clinically significant differences in patients with renal failure, so no dose adjustment usually needed for renal impairment 1
Understanding metoprolol's metabolism is crucial for optimizing therapy, particularly in patients with genetic variations in CYP2D6 activity or those taking medications that may interact with its metabolic pathway.