How is metoprolol (beta-blocker) cleared from the body?

Metoprolol Clearance from the Body

Metoprolol is primarily eliminated through hepatic metabolism (approximately 95%), with only a small portion (less than 10% in most individuals) excreted unchanged in the urine. 1

Metabolic Pathway

Metoprolol undergoes extensive hepatic metabolism primarily via the CYP2D6 enzyme system:

• The drug is extensively metabolized in the liver, with approximately 95% of the dose recoverable in urine as metabolites 1
• In normal metabolizers (extensive metabolizers), less than 10% of an intravenous dose is excreted as unchanged drug in the urine 1
• In poor CYP2D6 metabolizers (approximately 8% of Caucasians and 2% of other populations), up to 30-40% of oral or intravenous doses may be excreted unchanged 1, 2

Genetic Variability in Metabolism

CYP2D6 genetic polymorphism significantly impacts metoprolol clearance:

• Elimination half-life varies based on CYP2D6 metabolizer status:
  • Normal (extensive) metabolizers: 3-4 hours
  • Poor metabolizers: 7-9 hours 1, 2
• A meta-analysis demonstrated marked differences between metabolizer phenotypes:
  • 5.9-fold difference in oral clearance between extensive and poor metabolizers
  • 15-fold difference in oral clearance between ultrarapid and poor metabolizers 2
• Metoprolol exhibits stereoselective metabolism with approximately 40% greater R- than S-metoprolol metabolism in ultrarapid and extensive metabolizers 2

Special Populations

Renal Impairment

• The systemic availability and half-life of metoprolol in patients with renal failure do not differ significantly from those in normal subjects 1
• No dosage adjustment is typically needed in patients with chronic renal failure 1
• While metoprolol itself is not significantly affected by renal impairment, its metabolites may accumulate in severe renal dysfunction 3

Hepatic Impairment

• Hepatic impairment significantly impacts metoprolol pharmacokinetics 1
• In patients with cirrhosis:
  • Elimination half-life is prolonged to approximately 7.2 hours (vs. 4.2 hours in healthy controls)
  • Systemic bioavailability increases to 84% (vs. 50% in healthy controls) due to reduced first-pass metabolism 4
  • Total clearance correlates with markers of liver function such as galactose clearance and serum bilirubin 4

Elderly Patients

• Geriatric populations may show slightly higher plasma concentrations due to:
  • Decreased metabolism of the drug
  • Decreased hepatic blood flow
  • However, these increases are not clinically significant enough to warrant routine dose adjustments 1

First-Pass Metabolism

Metoprolol undergoes significant first-pass metabolism:

• Oral bioavailability is approximately 50% due to pre-systemic metabolism 1
• First-pass metabolism occurs primarily in the liver rather than the intestine:
  • Hepatic first-pass extraction is estimated at 48%
  • Intestinal first-pass extraction is minimal at approximately 0.85% 5
• Pre-systemic metabolism is saturable, leading to non-proportionate increases in exposure with increased doses 1

Clinical Implications

• Metoprolol is classified as "slightly dialyzable" during hemodialysis, with removal of less than 10% of an ingested dose 6
• Unlike beta-blockers with predominantly renal clearance (atenolol, nadolol, sotalol), metoprolol's hepatic metabolism makes it less affected by renal impairment 6, 7
• Due to its high endogenous clearance and volume of distribution, metoprolol will not be removed meaningfully by extracorporeal treatment modalities 6

Understanding metoprolol's clearance mechanism is important for appropriate dosing in patients with organ dysfunction, particularly those with hepatic impairment or CYP2D6 genetic variations.