Metabolism and Excretion of Metoprolol and Amiodarone
Metoprolol
Metabolism
Metoprolol is primarily metabolized by the CYP2D6 enzyme in the liver, with approximately 95% of the dose undergoing hepatic biotransformation. 1
- Metoprolol undergoes extensive first-pass metabolism, resulting in an oral bioavailability of approximately 50% in extensive metabolizers. 1
- The drug exhibits stereoselective metabolism dependent on CYP2D6 oxidation phenotype, with the R- and S-enantiomers metabolized differently. 1
- CYP2D6 genetic polymorphism significantly impacts metoprolol metabolism: poor metabolizers (approximately 8% of Caucasians and 2% of other populations) exhibit several-fold higher plasma concentrations compared to extensive metabolizers. 1
- In poor metabolizers, the elimination half-life extends to 7-9 hours compared to 3-4 hours in extensive metabolizers. 1
- Metoprolol has a high hepatic extraction ratio, meaning its clearance depends primarily on hepatic blood flow, which decreases with age. 2
Excretion
Less than 10% of metoprolol is excreted unchanged in urine in extensive metabolizers, while poor metabolizers may excrete 30-40% unchanged. 1
- Approximately 95% of the dose is recovered in urine, primarily as inactive metabolites. 1
- Renal clearance does not exhibit stereoselectivity, and renal impairment does not significantly affect metoprolol pharmacokinetics. 1
- The metabolites excreted by the kidneys appear to have no beta-blocking activity. 1
Clinical Implications
- In patients with hepatic cirrhosis, oral bioavailability increases to 84% (compared to 50% in healthy subjects) due to reduced first-pass metabolism, though total body clearance changes are not statistically significant. 3
- Dose adjustments may be required in elderly patients due to decreased hepatic blood flow. 2
Amiodarone
Metabolism
Amiodarone is metabolized to its major active metabolite, N-desethylamiodarone (DEA), primarily by CYP3A4 and CYP2C8 enzymes in both the liver and intestines. 4
- Amiodarone is highly lipophilic, resulting in increased volume of distribution and prolonged half-life, particularly in women and elderly patients. 2
- The CYP3A4 isoenzyme's presence in both liver and intestines contributes to the highly variable systemic availability of oral amiodarone due to large interindividual variability in CYP3A4 activity. 4
- DEA concentrations typically reach levels similar to amiodarone with prolonged therapy, though DEA serum concentrations above 0.05 mg/L are not usually seen until after several days of continuous infusion. 4
- Amiodarone is highly protein-bound (>96%). 4
Excretion
Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion, with negligible urinary excretion of either amiodarone or DEA. 4
- Neither amiodarone nor DEA is dialyzable. 4
- Renal impairment does not influence amiodarone pharmacokinetics. 4
- Both amiodarone and DEA cross the placenta and appear in breast milk. 4
Clinical Implications
- In cirrhotic patients, significantly lower peak and average concentrations of DEA are observed, but mean amiodarone levels remain unchanged. 4
- Elderly patients (>65 years) show lower clearances (approximately 100 mL/h/kg versus 150 mL/h/kg in younger subjects) and increased terminal half-life from approximately 20 to 47 days. 4
- In patients with severe left ventricular dysfunction, amiodarone pharmacokinetics are not significantly altered, but the terminal disposition half-life of DEA is prolonged. 4
- Close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction, though no specific dosage adjustment has been defined for patients with renal, hepatic, or cardiac abnormalities during chronic treatment. 4