From the Guidelines
Propranolol is primarily metabolized by the liver. This beta-blocker undergoes extensive first-pass metabolism in the liver, where it is broken down by hepatic enzymes. The liver converts propranolol into several metabolites, and only a small amount of propranolol is excreted unchanged in the urine, meaning the kidneys play a minimal role in its elimination [ 1 ].
Key Points
- Propranolol has a high hepatic extraction ratio, which means its clearance depends primarily on the hepatic blood flow [ 1 ].
- Hepatic blood flow decreases with age, thus dose adjustments may be required to minimize the risk of adverse drug reactions (ADRs) in older individuals [ 1 ].
- The liver's capacity to metabolize propranolol is crucial, and patients with liver disease may require dosage adjustments due to their compromised ability to break down the medication [ 1 ].
Clinical Implications
- Patients with liver disease may be at risk of higher blood levels and increased side effects due to the extensive hepatic metabolism of propranolol [ 1 ].
- Kidney impairment generally does not significantly affect propranolol clearance, though caution is still advised in severe renal dysfunction [ 1 ].
- Healthcare providers should carefully monitor patients with liver disease and adjust propranolol dosages as needed to minimize the risk of ADRs [ 1 ].
From the FDA Drug Label
Propranolol is extensively metabolized by the liver In a study conducted in 6 patients with cirrhosis and 7 healthy subjects receiving 160 mg of a long-acting preparation of propranolol once a day for 7 days, the steady-state propranolol concentration in patients with cirrhosis was increased 2.5-fold in comparison to controls. Propranolol is metabolized through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation), N-dealkylation followed by further side-chain oxidation, and direct glucuronidation The four major metabolites are propranolol glucuronide, naphthyloxylactic acid and glucuronic acid, and sulfate conjugates of 4-hydroxy propranolol In-vitro studies have indicated that the aromatic hydroxylation of propranolol is catalyzed mainly by polymorphic CYP2D6. Propranolol is primarily metabolized by the liver. The liver plays a significant role in the metabolism of propranolol, with the drug undergoing extensive hepatic metabolism. The kidneys also play a role in the elimination of propranolol metabolites, but the primary site of metabolism is the liver 2.
From the Research
Metabolism of Propranolol
- Propranolol is primarily metabolized by the liver, with the drug being cleared very efficiently by the liver after intravenous administration 3.
- The liver's ability to metabolize propranolol is dependent on liver blood flow, and both bound and free forms of the drug are extracted by the liver 3.
- Propranolol is metabolized into several active metabolites, including 4-hydroxypropranolol and N-desisopropylpropranolol, with the formation rates of these metabolites varying between individuals 4.
Role of Cytochrome P450 Isozymes
- Cytochrome P450 isozymes, particularly CYP2D6 and CYP1A2, play a crucial role in the metabolism of propranolol in human liver microsomes 5.
- CYP2D6 is involved in the ring-hydroxylation of propranolol, while CYP1A2 is involved in the N-desisopropylation of the drug 5.
- Propranolol has been shown to inhibit certain cytochrome P450-dependent monooxygenase activities in rat liver microsomes, including those involved in the metabolism of other drugs 6.