What is Nabumetone (Nabutone)?

What is Nabumetone?

Nabumetone is a non-acidic, non-steroidal anti-inflammatory drug (NSAID) that functions as a prodrug, converting in the liver to its active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA), which preferentially inhibits COX-2 and provides anti-inflammatory, analgesic, and antipyretic effects. 1

Chemical Structure and Formulation

• Nabumetone is chemically designated as 4-(6-methoxy-2-naphthalenyl)-2-butanone, a naphthylalkanone compound with a molecular weight of 228.3 1
• It is a white or almost white crystalline substance that is non-acidic, freely soluble in acetone, sparingly soluble in alcohol and methanol, but practically insoluble in water 1
• Available as oral tablets in 500 mg and 750 mg strengths 1

Mechanism of Action

• Nabumetone itself is pharmacologically inactive and must undergo hepatic biotransformation to its active metabolite 6-MNA, which is a potent inhibitor of prostaglandin synthesis 1
• The active metabolite 6-MNA preferentially inhibits cyclo-oxygenase-2 (COX-2) over COX-1, which may contribute to its favorable gastrointestinal safety profile 2, 3
• Approximately 35% of an oral dose is converted to 6-MNA, while 50% is converted to unidentified metabolites that are subsequently excreted 1

Pharmacokinetics

• After oral administration, approximately 80% of a radiolabeled dose is found in urine, indicating excellent gastrointestinal absorption 1
• Nabumetone itself is not detected in plasma because it undergoes rapid first-pass metabolism to 6-MNA 1, 2
• The active metabolite 6-MNA is more than 99% bound to plasma proteins, with the free fraction being 0.2-0.3% at typical therapeutic concentrations 1
• The elimination half-life of 6-MNA is 22.5-29.8 hours, allowing for once-daily dosing 1
• Food increases the rate of absorption and peak plasma concentrations of 6-MNA by approximately one-third, but does not affect the extent of conversion 1
• Unlike other NSAIDs, there is no evidence of enterohepatic recirculation of the active metabolite 1, 3

Clinical Indications

• Nabumetone is FDA-approved for relief of signs and symptoms of osteoarthritis and rheumatoid arthritis 1
• The optimum oral dosage for osteoarthritis is 1 g once daily 2
• For rheumatoid arthritis, 1 g at bedtime is optimal, with an additional 0.5-1 g in the morning for patients with persistent symptoms 2
• Clinical efficacy has also been evaluated in ankylosing spondylitis, soft tissue injuries, and juvenile rheumatoid arthritis 2

Comparative Efficacy

• Nabumetone demonstrates comparable clinical efficacy to aspirin, diclofenac, piroxicam, ibuprofen, naproxen, indomethacin, and sulindac in treating rheumatoid arthritis and osteoarthritis 2, 4, 5
• Therapeutic response is superior to placebo and similar to nonselective COX inhibitors 2

Safety Profile

Gastrointestinal Safety

• Nabumetone has a favorable gastrointestinal safety profile compared to other nonselective NSAIDs, with rates of gastrointestinal ulceration and bleeding less than 1% annually 2, 4
• The low incidence of gastrointestinal perforations, ulcerations, and bleeding is attributed to its non-acidic chemical properties and preferential COX-2 inhibition profile 2
• Ibuprofen, etodolac, and nabumetone demonstrate superior gastrointestinal safety compared to other NSAIDs 6

Other Safety Considerations

• Most frequent adverse effects include diarrhea, dyspepsia, headache, abdominal pain, and nausea 2
• Nabumetone has a dose-related effect on platelet aggregation but no effect on bleeding time in clinical studies 2
• Short-term studies show little to no effect on renal function 2
• Like all NSAIDs, nabumetone carries cardiovascular risks including myocardial infarction, stroke, heart failure, and hypertension 6

Special Populations

• Elderly patients with osteoarthritis demonstrate decreased elimination and increased plasma concentrations compared to young healthy volunteers 7
• Renal failure significantly reduces 6-MNA elimination, though steady-state concentrations are not increased due to nonlinear protein binding 7
• Reduced bioavailability of 6-MNA occurs in patients with severe hepatic impairment 7
• Dosage adjustment may be required in the elderly, patients with active rheumatic disease, and those with hepatic impairment 7

Clinical Context Among NSAIDs

• Nabumetone is listed among therapeutic NSAIDs alongside ibuprofen, naproxen, tolmetin, indomethacin, meloxicam, diclofenac, piroxicam, etodolac, and celecoxib in rheumatology guidelines 8
• It has been used successfully as an alternative NSAID for patients with aspirin allergy in conditions like erythromelalgia 8
• The half-life of nabumetone is approximately 20 hours, placing it among the longer-acting NSAIDs like meloxicam and piroxicam 8