Nabumetone

Nabumetone contains an active substance 4-(6'-methoxy-2’naphthyl)-2 butanone.

Nabumetone is a non acidic non steroidal anti-inflammatory agent with weak prostaglandin synthesis properties. A notable feature of the animal pharmacology is the lack of effect on the gastric mucosa. Nabumetone is well absorbed from the gastro-intestinal tract and undergoes rapid and extensive metabolism in the liver to 6-methoxy-2-naphthylacetic acid (6-MNA), the principal active metabolite which is a potent inhibitor of prostaglandin synthesis.

Nabumetone has a weak effect on platelet aggregation caused by collagen and no effect on bleeding time.

In humans, lower frequency of peptic ulcers, bleeding or perforation has been reported in comparison with other NSAIDs.

Although nabumetone is well absorbed from the GI tract (>80%), concentrations in the plasma are too small to be measured as extensive metabolism occurs during the first pass through the liver to the active metabolite 6-methoxy-2-napthylacetic acid (6-MNA) and other inactive metabolites. Intravenous studies in rats with nabumetone indicate it to be rapidly distributed throughout the body, in keeping with its highly lipophilic character. The active metabolite 6-MNA is distributed into inflamed tissue and crosses the placenta into foetal tissue. It is found in the milk of lactating females.

The absorption rate is increased by concurrent ingestion of food or milk. However, the total quantity of the active metabolite in plasma is unchanged. In-vivo studies suggest that 6-MNA does not undergo any enterohepatic circulation. The bioavailability of 6-MNA in administration of nabumetone is approximately 23-52%. The maximum plasma level of 6-MNA is reached at around 3 (1-12) hours after dosing.

The free fraction is dependent on the total concentration of 6-MNA and is proportional to dose in the range 1-2 g. The free fraction is 0.2-0.3% for 1 g daily dosing and approximately 0.6-0.8% with 2 g daily dosing. Because of its strong binding to proteins, 6-MNA cannot be dialysed.

6-MNA is more than 99% bound to plasma protein and diffuses into synovial fluid.

Following intravenous administration, the distribution volume has been measured as 7.5 (6.8-8.4) l and clearance as 4.4 (1.0-6.9) ml/min.

The plasma elimination half-life of 6-MNA varies considerably (mean values reported in young adults of approx. 22 to 27 hours and approx. 25 to 34 hours in the elderly).

6-MNA undergoes further metabolism by conjugation with glucuronic acid followed by O-methylation and conjugation before being excreted mainly in the urine.

Elderly

The steady-state plasma concentration in the elderly is usually higher and the half-life longer (29.8±8.1 hours) than in young healthy individuals, but the different intervals overlap to a great extent.

Renal Impairment

In patients with severely impaired renal function (creatinine clearance <30 ml/min), the mean value of the half-life of 6-MNA increased to around 40 hours and the plasma levels are 30% higher than in other patients. In patients who underwent dialysis, the steady-state plasma concentration of the active metabolite was equivalent to the values observed in healthy individuals.

No data.