Nabumetone is a highly powerful and selective COX-2 inhibitor. Nabumetone (50 μmol-2 mmol) decreases proliferation of K-562 and Meg-01 cells in a dose-dependent manner, but has no apparent apoptotic impact. Nabumetone enhances the apoptotic impact of ADR in the K-562 cell line. Furthermore, Nabumetone lowers Bcl-2 expression[1].

In rats, napumetone (79 mg/kg, po) reduces PGE2 exudate from the paws and paw oedema. In rats, napumetone only inhibits the generation of 6-keto-PGF1α from the gastric mucosa by 57% and does not cause any harm to the stomach[2]. In rats, napumetine (25, 50, and 100 mg/kg, i.p.) enhances mucus secretion generated by stress and dose-dependently prevents the rise in DDC-induced mucus secretion. Rats' stress-induced ulcer index is dramatically suppressed by napumetone (25 mg/kg, ip)[3].

Absorption, Distribution and Excretion
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.
Most drug is eliminated via hepatic metabolism with minimal to no parent drug detectable in the plasma. 80% of the dose is then excreted by the kidneys and 10% in the feces. It does not appear to undergo enterohepatic recirculation.
The Vd of 6-MNA reported after administration of a single dose is 0.1-0.2 L/kg or approximately 5-10 L. Vdss reported in official product labeling is approximately 53 L.
6-MNA has an apparent steady-state clearance of 20 - 30 mL/min.

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Metabolism / Metabolites
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.
Nabumetone has known human metabolites that include 4-hydroxy-4-(6-methoxynaphthalen-2-yl)butan-2-one.

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Biological Half-Life
6-MNA has a mean half-life of 24 hours with a range of 19-36 hours.

Hepatotoxicity
Prospective studies show that 1% to 5% of patients taking nabumetone experience at least transient serum aminotransferase elevations. These may resolve even with drug continuation. Marked aminotransferase elevations (>3 times ULN) occur in 0.5% of patients, a rate similar to that in placebo treated controls. Clinically apparent liver injury with jaundice from nabumetone is rare and in large clinical trials, no instances of acute liver injury with jaundice were reported. Since its approval and release, nabumetone has been reported to cause rare instances of serious hepatic adverse events (~1.3 per million prescriptions), but there have been no cases of clinically apparent liver injury due to nabumetone described in the published literature. Furthermore, nabumetone is not mentioned as a cause in large case series on drug induced liver injury or acute liver failure. Thus, the latency, clinical features and outcome of nabumetone induced liver injury have not been described and clinically apparent hepatotoxicity due to nabumetone must be very rare.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because no information is available on the use of nabumetone during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
6-MNA is over 99% bound to plasma proteins, likely albumin. The unbound fraction is 0.1-0.2% and remains proportional in the dose range of 1000-2000mg

[1]. Cyclo-oxygenase 2 inhibitor, nabumetone, inhibits proliferation in chronic myeloid leukemia cell lines. Leuk Lymphoma. 2005 May;46(5):753-6.

[2]. Anti-inflammatory and gastrointestinal effects of nabumetone or its active metabolite, 6MNA (6-methoxy-2-naphthylacetic acid): comparison with indomethacin. Agents Actions. 1992;Spec No:C82-3.

Pharmacodynamics
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.

C15H16O2

228.29

228.115

42924-53-8

Nabumetone-d3;1216770-08-9

4409

White to off-white solid powder

1.1±0.1 g/cm3

371.1±17.0 °C at 760 mmHg

80-81ºC

165.4±14.5 °C

0.0±0.8 mmHg at 25°C

1.576

2.82

0

2

4

17

262

0

BLXXJMDCKKHMKV-UHFFFAOYSA-N

InChI=1S/C15H16O2/c1-11(16)3-4-12-5-6-14-10-15(17-2)8-7-13(14)9-12/h5-10H,3-4H2,1-2H3

4-(6-methoxynaphthalen-2-yl)butan-2-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (9.11 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (9.11 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (9.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)