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General Description:

Acemetacin, identified by CAS number 53164-05-9, is a notable compound with significant therapeutic applications. Acemetacin is a carboxymethyl ester of indometacin. It is a potent non-steroidal anti-inflammatory drug, derived from the indol-3-acetic acid, whose activity is thought to be mainly through its active metabolite indomethacin. In clinical trials, acemetacin exhibits a better gastric tolerability compared to its active metabolite indometacin. It was developed by E. Merck and Company in Germany as an attempt to provide a safer drug but other than the amelioration on the gastrointestinal effects, the metabolism of acetamicin led to the formation of indomethacin and it kept the same side effects.

Indications:

This drug is primarily indicated for: Acemetacin is not FDA, Canada or EMA approved, but in the countries where it is marketed it is indicated for the symptomatic treatment of pain and swelling in acute inflammation of the joints in rheumathoid arthritis, osteoarthritis, low back pain and post-surgical pain. It is also indicated for the treatment of chronic inflammation of the joints in presence of rheumatoid arthritis, treatment of ankylosing spondylitis, treatment of irritation in the joints and spinal column caused by degenerative disorders, treatment of inflammatory soft-tissue rheumatism syndrome and painful swelling and inflammation caused by injury. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Acemetacin undergoes metabolic processing primarily in: Acemetacin is highly metabolized and degraded by esterolytic cleavage to form its major and active metabolite indometacin. It presents other inactive metabolites made by reaction of O-demethylation, N-desacylation and part of them are also transformed by conjugation with glucuronic acid. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Acemetacin are crucial for its therapeutic efficacy: After 8 days of oral administration twice daily of acemetacin there was an age-dependant Cmax of 276.8 ng/ml in elderly compared to 187 ng/ml for younger individuals. There was also a Tmax of 2.5 h and AUC in a range of 483-712 ng h/ml. The bioavailability of acemetacin after repeated doses is aproximately 66% in plasma and 64% in urine. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Acemetacin is an important consideration for its dosing schedule: The elimination half-life of acemetacin after steady-state is 4.5 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Acemetacin exhibits a strong affinity for binding with plasma proteins: Acemetacin is found highly bound to plasma proteins, reaching a percentage higher than 90% of the administered dose. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Acemetacin from the body primarily occurs through: The elimination of acemetacin is divided in renal elimination that covers 40% of the complete administered dose and the restant 60% is excreted in feces. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Acemetacin is distributed throughout the body with a volume of distribution of: The apparent volume of distribution of acemetacin is in a range of 0.5-0.7 L/kg. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Acemetacin is a critical factor in determining its safe and effective dosage: Intravenous administration of acemetacin in healthy subjects reported a clearance rate of 4.59 ml min/kg. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Acemetacin exerts its therapeutic effects through: The effect of acemetacin causes a weak reduction of prostaglandin synthesis which generates an anti-inflammatory and analgesic effect. The weak inhibition of prostaglandin reduces significantly the damage caused in the mucous membrane of the gastrointestinal tract. Studies have shown that acemetacin strongly inhibits the release of histamine from mast cells and the generation of hyperthermia. Acemetacin effect also causes changes in systolic and diastolic blood pressure as well as inhibition of platelet aggregation. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Acemetacin functions by: Acemetacin is a non-selective inhibitor of the production of pro-inflammatory mediators derived from the action of the enzyme COX. COX is essential for the synthesis of prostaglandin E2 and F2 which are molecules derived from fatty acids and stored in the cell membrane. Acetometacine is metabolized and forms its major metabolite indometacin which is also a non-selective inhibitor of COX and exhibits the capacity to inhibit the motility of polymorphonuclear leukocytes and decreased cerebral flow by modulating the nitric oxide pathway and vasoconstriction. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Acemetacin belongs to the class of organic compounds known as benzoylindoles. These are organic compounds containing an indole attached to a benzoyl moiety through the acyl group, classified under the direct parent group Benzoylindoles. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Indoles and derivatives class, specifically within the Benzoylindoles subclass.

Categories:

Acemetacin is categorized under the following therapeutic classes: Acetic Acid Derivatives and Related Substances, Agents causing hyperkalemia, Agents that produce hypertension, Analgesics, Analgesics, Non-Narcotic, Anti-Inflammatory Agents, Anti-Inflammatory Agents, Non-Steroidal, Antigout Preparations, Antiinflammatory and Antirheumatic Products, Antiinflammatory and Antirheumatic Products, Non-Steroids, Antirheumatic Agents, Heterocyclic Compounds, Fused-Ring, Indoles, Musculo-Skeletal System, Nephrotoxic agents, Non COX-2 selective NSAIDS, Peripheral Nervous System Agents, Sensory System Agents, UGT2B7 substrates. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Acemetacin include:

• Water Solubility: Slightly soluble
• Melting Point: 151.5ºC
• Boiling Point: 637ºC
• logP: 4.49
• pKa: 2.6