Nabumetone

Absorption

Nabumetone is well-absorbed from the GI tract and undergoes significant first pass metabolism resulting in approximately 35% being converted to the active metabolite, 6-MNA. Tmax for 6-MNA varies widely with a mean values of 3 and 11 hours reported in official product monographs, and described as 9-12 hours in published literature Administration with food increases Cmax by 33% and increases absorption rate. If formulated as a suspension the Cmax increases and the Tmax is reduced by 0.8 hours while the all other pharmacokinetic parameters remain unchanged.

Toxicity

LD50 Values
Mouse: 4290 mg/kg (Oral), 2380 mg/kg (IP)
Rat: 3880 mg/kg (Oral), 1520 mg/kg (IP), >10 g/kg (SC)
Monkey: 3200 mg/kg (Oral)
Overdose
Signs and symptoms of nabumetone overdose include lethargy, drowsiness, nausea, vomiting, and epigastric pain. These are considered reversible with supportive care. GI bleeding, hypertension, acute kidney injury, respiratory depression, and coma are rare but can occur. No antidote exists for nabumetone overdose although administration of activated charcoal and/or induction of emesis can reduce absorption if the nabumetone dose was taken less than 4 hours prior. 6-MNA is cannot be cleared by dialysis.
Carcinogenicity & Mutagenicity
Nabumetone was not significantly carcinogenic in rats or mice studied over 2 years. Neither the Ames test nor mouse micronucleus test showed nabumetone or it's active metabolite, 6-MNA, to be mutagenic. Chromosomal abberation has been observed in cultured lymphocytes exposed to concentrations of 80 mcg/mL and higher of nabumetone or 6-MNA equivalent to the maximum recommended human dose.
Reproductive Toxicity
No adverse effects on fertility have been observed in male and female rats at doses of 320 mg/kg/day.] No teratogenicity has been observed in pregnant rabbits or rats. Dystocia and delayed parturition have been noted in rats resulting in reduced survival of offspring. This has been attributed to the role of prostaglandins in uterine contraction. NSAIDs can also cause premature closure of the ductus ateriosus.
Lactation
6-MNA has been detected in the milk of lactating rats. While no data is available in humans, 6-MNA is both highly protein bound and exists in its anionic form in circulation. For these reasons partitioning into breast milk is expected to be limited.

Description

Nabumetone is a non-acidic, nonsteroidal antiinflammatory agent formally related to naproxen. Its main circulating metabolite is 6-methoxy-2-naphthylacetic acid (α-nornaproxen). Administered once daily (Tsub>1/2 * 30 hrs), nabumetone is reported to be effective in the treatment of rheumatoid and osteoarthritis.

Chemical properties

White Powder

Originator

Beecham (United Kingdom)

The Uses of Nabumetone

Nabumetone is an anti-inflammatory and antibacterial agent (1). A non-steroidal anti-inflammatory prodrug used for treatment of inflammatory and degenerative rheumatic diseases.

The Uses of Nabumetone

Anti-inflamatory. Antibacterial

The Uses of Nabumetone

Anti-inflammatory. Antibacterial.

The Uses of Nabumetone

anesthetic (local)

Indications

Indicated for:
1) Symptomatic relief in rheumatoid arthritis.
2) Symptomatic relief in osteoarthritis.

Background

Nabumetone was originally developed as a non-acidic non-steroidal anti-inflammatory drug (NSAID). It was thought to avoid trapping of the drug in the stomach by making it unable to dissociate into ions which was believed to reduce GI toxicity by limiting local action. While slightly reduced, possibly due to a degree of cyclooxygenase-2 selectivity (COX-2), nabumetone still produces significant adverse effects in the GI tract. The molecule itself is a pro-drug with its 6-methoxy-2-naphthylacetic acid (6-MNA) metabolite acting as a potent COX inhibitor similar in structure to naproxen. Nabumetone was developed by Smithkline Beecham under the trade name Relafen and first received FDA approval in December, 1991.

What are the applications of Application

Nabumetone is a non-steroidal COX II inhibitor that reduces production of prostaglandins

Definition

ChEBI: A methyl ketone that is 2-butanone in which one of the methyl hydrogens at position 4 is replaced by a 6-methoxy-2-naphthyl group. A prodrug that is converted to the active metabolite, 6-methoxy-2-naphthylacetic acid, following oral administration. It is s own to have a slightly lower risk of gastrointestinal side effects than most other non-steroidal anti-inflammatory drugs.

Indications

Nabumetone (Relafen) is approved for rheumatoid arthritis, osteoarthritis, and pain management. Its long half-life allows for once-daily dosing. Although this drug is a weak inhibitor of COX, it is metabolized in the liver to 6-methoxy-2-naphthylacetic acid (6-MNA), a strong COX inhibitor that is chemically similar to naproxen. As with most NSAIDs, GI side effects are most commonly reported. The incidence of gastric ulceration is lower with nabumetone than with many other NSAIDs.This is due to its nature as a prodrug, not to COX-2 selectivity. Lower-bowel complaints, rashes, and CNS disturbances are common adverse effects.

Manufacturing Process

4-(5-Bromo-6-methoxy-2-naphthyl)-4-hydroxybut-3-en-2-one
50 grams (0.179 moles) of 2-acetyl-5-bromo-6-methoxynaphthalene and 200 ml of n-butyl acetate are placed in a flask equipped with refrigerator and stirrer and, under stirring and at the temperature of 15°C, 14.5 g (0.268 moles) of sodium methoxide are added. The temperature of the reaction mixture goes up to 25°C and is kept at this value for 30 minutes, then the mixture is warmed at 65°C for one hour, is added with 100 ml of water and is brought to pH 4 by adding a concentrated aqueous solution of hydrochloric acid. The reaction mixture is then cooled to 0°-5°C and kept at this temperature for one hour. The solid is filtered, abundantly washed with water on the filter, then washed with butyl acetate and dried in oven under vacuum obtaining 53 g of product with a yield equal to 92%.
Example 1. 4-(6-Methoxy-2-naphthyl)butan-2-one
48 grams (0.150 moles) of 4-(5-bromo-6-methoxy-2-naphthyl)-4-hydroxybut- 3-en-2-one, 6.1 g of sodium acetate hydrate containing 32.4% of water, equivalent to 0.050 moles of sodium acetate, 4 g of a 50% suspension in water of 10% palladium on carbon, equivalent to 0.0019 moles of palladium, and 500 ml of methanol are put in a hydrogenator. The hydrogenator is washed with nitrogen in order to eliminate the oxygen and then hydrogen is introduced at the pressure of 2 atmospheres. The temperature of reaction is kept at 40°C for a period of time of 6 hours, then the hydrogen is let off, the hydrogenator is washed with nitrogen and the reaction mixture is filtered to eliminate the catalyst. The solution is brought to pH 6 with a 5% aqueous solution of sodium hydroxide and concentrated under vacuum. The oily residue is dissolved into 130 ml of isopropanol and 30 ml of N,Ndimethylformamide and the solution is added with 45 ml of water and 17.6 g of sodium bisulfite obtaining a suspension that is stirred for one hour at 60°C, then is cooled to 5°C and is filtered. The obtained solid is washed with 75 ml of methanol, suspended in 200 ml of a 5% aqueous solution of sodium hydroxide and kept under stirring at room temperature for three hours. The suspension is then filtered, the solid is washed with water until neutrality and dried in oven under vacuum obtaining 18 g of product with a yield equal to 52.8%.
Example 2. 4-(6-Methoxy-2-naphthy)butan-2-one
The reaction described above is repeated with the sole changes of doubling the amount of sodium acetate hydrate containing 32.4% of water, 12.22 g equivalent to 0.100 moles of sodium acetate, and of lowering the hydrogenation time to five hours. In this way 22.5 g of product are obtained with a yield equal to 66%.
Example 3. 4-(6-Methoxy-2-naphthyl)butan-2-one
The reaction described in example 3 is repeated with the sole changes of nearly triplicating the amount of sodium acetate hydrate containing 32.4% of water, 17.60 g equivalent to 0.145 moles of sodium acetate, and of lowering the hydrogenation time to five hours. The oil obtained by evaporating the solvent at the end of the reaction is treated with 300 ml of toluene and 100 ml of water and after 15 minutes of stirring the two layers are separated. The aqueous phase is discarded while the organic phase is evaporated under vacuum at 70°C obtaining an oil that is dissolved into 100 ml of methanol. The solution is kept at 0°C for two hours and the precipitated solid is filtered, washed with 15 ml of methanol cooled to 0°C and dried in oven under vacuum. In this way 21.7 g of product are obtained. The methanolic filtrates from crystallization and washing are concentrated under vacuum to half volume so obtaining, after cooling to 0°C, the crystallization of other 4 g of product with an overall yield equal to 75.3%.

brand name

Relafen (Smith-Kline Beecham);RELIFEX.

Therapeutic Function

Antiinflammatory

General Description

Nabumetone (Relafen), a nonacidic NSAID prodrug, isclassified as an arylacetic acid, because it undergoes rapidhepatic metabolism to its active metabolite, 6-methoxy-2-naphthylacetic acid. Similar to the other arylacetic aciddrugs, it is used in short- or long-term management of RAand OA. Being nonacidic, it does not produce significantprimary insult to the GI mucosa lining and also has no effecton prostaglandin synthesis in gastric mucosa, thus producingminimum secondary GI damage when comparedwith other conventional NSAIDs.

Pharmacokinetics

NSAIDs, like nabumetone, are well established as analgesics. NSAIDs reduce both peripheral and central sensitization of nociceptive neurons due to inflammation which contribute to hyperalgesia and allodynia. This sensitization occurs through reducing the action potential threshold in peripheral neurons, reducing the intensity of painful stimuli needed to produce a painful sensation. Centrally, activation of dorsal horn neurons occurs along with increased release of glutamate, calcitonin gene-related peptide (CGRP), and substance P which increase the transmission of painful stimuli. Coupled with this is an inhibition glycinergic neurons which normally inhibit pain transmission, a phenomenon known as disinhibition. Increased activity ofn-methyl d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors leads to the establishment of central sensitization, allowing both mild painful and innocuous stimuli to produce action potentials in nociceptive projection neurons. NSAIDs are effective in reducing mild-moderate acute and chronic nociceptive pain, however, the usefulness of NSAIDs in neuropathic pain is limited.
The anti-inflammatory effect of NSAIDs is mediated by preventing vasodilation, increases in vascular permeability, and the release of cytokines from endothelial cells. These three effects together prevent immunocompetent cells from migrating to the site of injury thereby preventing additional damage and inflammation due to activation of the immune system at the site of damage. PGs also modulate T-helper cell activation and differentiation, an activity which is thought to be of importance in arthritic conditions.
The anti-pyretic effect of NSAIDs is mediated through preventing increases in temperature by prostaglandins (PGs) via the hypothalamus. Activation of this process by other inflammatory mediators relies upon subsequent action by PGs, therefore NSAIDs are able to reduce fever due to these mediators as well.
The adverse effects of NSAIDs are related to their therapeutic effects. The same vasodilatory action which occurs in inflammation also serves to regulate blood flow to the kidneys through the afferent renal arteries. NSAIDs are widely known as nephrotoxic agents as the reduction in PGs produces vasoconstriction of these arteries resulting in reduced blood flow to the kidneys and a subsequent decline in renal function. Reductions in mucus and HCO3- secretion in the stomach increases the risk of ulceration by limiting the protection mediated by PGs. Lastly, COX-2 selective agents like nabumetone can unbalance prothrombotic and antithrombotic prostanoid generation leading to increased platelet aggregation and increased risk of thrombosis.

Pharmacokinetics

Nabumetone is absorbed primarily from the duodenum. Milk and food increase the rate of absorption and the bioavailability of the active metabolite. Plasma concentrations of unchanged drug are too low to be detected in most subjects after oral administration, so most pharmacokinetic studies have involved the disposition of the active metabolite. Pharmacokinetic properties are altered in elderly patients, with higher plasma levels of the active metabolite being noted. Nabumetone undergoes rapid and extensive metabolism in the liver, with a mean absolute bioavailability of the active metabolite of 38%. The metabolism of nabumetone is illustrated in Figure 36.15. The major, most active metabolite is 6MNA, but the initial alcohol metabolite, a minor product, and its esters also possess significant anti-inflammatory properties.

Clinical Use

Nabumetone is indicated for the acute and chronic treatment of the signs and symptoms of osteoarthritis and rheumatoid arthritis. The recommended starting dosage is 1,000 mg as a single dose with or without food. More symptomatic relief of severe or persistent symp-toms may be obtained at doses of 1,500 or 2,000 mg/day

Drug interactions

Potentially hazardous interactions with other drugs
ACE inhibitors and angiotensin-II antagonists: antagonism of hypotensive effect; increased risk of nephrotoxicity and hyperkalaemia
Analgesics: avoid concomitant use of 2 or more NSAIDs, including aspirin (increased side effects); avoid with ketorolac (increased risk of side effects and haemorrhage).
Antibacterials: possibly increased risk of convulsions with quinolones.
Anticoagulants: effects of coumarins and phenindione enhanced; possibly increased risk of bleeding with heparin, dabigatran and edoxaban - avoid long term use with edoxaban.
Antidepressants: increased risk of bleeding with SSRIs and venlaflaxine.
Antidiabetic agents: effects of sulphonylureas enhanced.
Antiepileptics: possibly increased phenytoin concentration.
Antivirals: increased risk of haematological toxicity with zidovudine; concentration possibly increased by ritonavir.
Ciclosporin: may potentiate nephrotoxicity. Cytotoxics: reduced excretion of methotrexate; increased risk of bleeding with erlotinib.
Diuretics: increased risk of nephrotoxicity; antagonism of diuretic effect; hyperkalaemia with potassium-sparing diuretics.
Lithium: excretion decreased.
Pentoxifylline: increased risk of bleeding.
Tacrolimus: increased risk of nephrotoxicity.

Metabolism

Nabumetone is reduced to 3-hydroxy nabumetone by the aldo-keto reductase-1C family and by corticosteroid 11-beta-dehydrogenase. It then undergoes oxidative cleavage by CYP1A2 to 6-MNA, the active metabolite. 6-MNA is eliminated by O-demethylation by CYP2C9 to 6-hydroxy-2-naphthylacetic acid (6-HNA). Both 6-MNA and 6-HNA are further converted to conjugates. Other metabolites are generated through a mix of ketone reduction and O-demethylation along with subsequent conjugation. Glucuronide conjugates of several metabolites have been found to become further conjugated to glycine residues.

Metabolism

Nabumetone is rapidly metabolised in the liver to the main active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA). The metabolite is a potent inhibitor of prostaglandin synthesis. Excretion of the metabolite is predominantly in the urine.