Are acetaminophen and ibuprofen metabolized by the liver and excreted by the kidneys?

Acetaminophen and Ibuprofen Metabolism and Excretion

Yes, acetaminophen is extensively metabolized by the liver and its metabolites are excreted by the kidneys. Ibuprofen follows a similar pattern of hepatic metabolism followed by renal excretion.

Acetaminophen Metabolism and Excretion

Hepatic Metabolism

• Acetaminophen undergoes extensive hepatic metabolism, with 85-95% of a therapeutic dose being metabolized predominantly in the liver 1
• The major metabolic pathways include sulfation (catalyzed by SULT1A1, 1A3/4, and 1E1) and glucuronidation (catalyzed by UGT1A1 and 1A6), which together account for the majority of drug elimination 2
• A minor fraction (approximately 5-10%) is oxidized by cytochrome P450 enzymes (primarily CYP2E1, with contributions from CYP3A4 and CYP1A2) to form the reactive metabolite N-acetyl-p-benzoquinone-imine (NAPQI) 2, 3
• NAPQI is normally conjugated with glutathione and further metabolized to cysteine and mercapturic acid conjugates for excretion 1, 3

Renal Excretion

• Within 24 hours of therapeutic dosing, 85-95% of acetaminophen is excreted in the urine as metabolites: approximately 4% as unchanged drug, 55% as glucuronide conjugate, 30% as sulfate conjugate, and 4% each as mercapturic acid and cysteine conjugates 1
• The metabolites are actively transported out of hepatocytes via canalicular transporters (Mrp2 and Bcrp) and basolateral transporters (Mrp3 and Mrp4) before renal excretion 2
• Acetaminophen metabolism also occurs to some extent in the kidney itself via renal P450 enzymes 4

Clinical Implications for Hepatic and Renal Function

• Acetaminophen carries significant hepatic toxicity risk, particularly with overdoses exceeding 2,000 mg/kg, which can lead to liver failure, liver transplant, or death 5
• The plasma half-life of 1.9-2.5 hours is prolonged in patients with decompensated liver disease but remains normal in mild chronic liver disease 1
• Renal toxicity can occur with acute overdoses (>2,000 mg/kg), characterized by proximal tubule injury and reduced glomerular filtration rate, though chronic therapeutic use alone does not appear to cause classic analgesic nephropathy 4
• Factors that enhance renal toxicity include chronic liver disease, concurrent renal insults, and conditions altering P450 enzyme activity 4

Important Caveats

• The FDA has mandated limiting acetaminophen to 325 mg per dosage unit in prescription combination products to reduce overdose risk and severe liver injury 5
• Acetaminophen should be used with extreme caution in patients with compromised hepatic or renal function, and total daily doses from all sources should not exceed 3,000-4,000 mg 6
• Recent attention has been drawn to the relative limited efficacy and significant adverse effects of acetaminophen, particularly hepatic and renal toxicity, compounded by its inclusion in numerous prescription opioid preparations and over-the-counter products 5

Ibuprofen Metabolism and Excretion

General Metabolic Pattern

• NSAIDs, including ibuprofen, should be prescribed with caution in patients older than 60 years or in the presence of compromised fluid status, renal insufficiency, concomitant administration of other nephrotoxic drugs, and renally excreted chemotherapy to prevent renal toxicities 5
• While the provided evidence does not contain detailed pharmacokinetic data specifically for ibuprofen, NSAIDs as a class undergo hepatic metabolism and renal excretion, with particular concern for renal toxicity in vulnerable populations 5