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General Description:

Loteprednol etabonate, identified by CAS number 82034-46-6, is a notable compound with significant therapeutic applications. Loteprednol Etabonate (LE) is a topical corticoid anti-inflammatory. It is used in ophthalmic solution for the treatment of steroid responsive inflammatory conditions of the eye such as allergic conjunctivitis, uveitis, acne rosacea, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, and selected infective conjunctivitides. As a nasal spray, it can be used for the treatment and management of seasonal allergic rhinitis. Most prescription LE products, however, tend to be indicated for the treatment of post-operative inflammation and pain following ocular surgery . A number of such new formulations that have been approved include Kala Pharmaceutical's Inveltys - the first twice-daily (BID) ocular corticosteroid approved for this indication, designed specifically to enhance patient compliance and simplified dosing compared to all other similar ocular steroids that are dosed four times daily . Moreover, LE was purposefully engineered to be a 'soft drug', one that is designed to be active locally at the site of administration and then rapidly metabolized to inactive components after eliciting its actions at the desired location, thereby subsequently minimizing the chance for adverse effects .

Indications:

This drug is primarily indicated for: A number of prescription loteprednol etabonate ophthalmic products are specifically indicated for the treatment of post-operative inflammation and pain following ocular surgery . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Loteprednol etabonate undergoes metabolic processing primarily in: Loteprednol etabonate (LE) is readily and extensively metabolized to two inactive metabolites, PJ-90 (Δ1-cortienic acid) and PJ-91 (Δ1-cortienic acid etabonate) . Metabolism occurs locally in ocular tissues, and to the extent that loteprednol etabonate reaches the systemic circulation, likely the liver and other tissues into which it distributes . In particular, studies have demonstrated that LE (chloromethyl 17alpha-ethoxycarbonyloxy-11beta-hydroxy-3-oxoandrosta-1,4-diene) is rapidly hydrolyzed at the location of its 17beta-chloromethyl ester function by paraoxonase 1 in human plasma at the site of administration at the level of the affected eye tissue to the 17beta-carboxylate PJ-91 metabolite and PJ-90 metabolite . Both metabolites are considered inactive . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Loteprednol etabonate are crucial for its therapeutic efficacy: Loteprednol etabonate (LE) demonstrates good ocular permeation properties as it is lipid soluble, allowing the agent to penetrate into cells with relative ease . Results from the ocular administration of loteprednol in normal, healthy volunteers have shown that there are low or undetectable concentrations of either unchanged material or its metabolite . Following twice-daily unilateral topical ocular dosing of LE for 14 days in healthy subjects, the plasma concentrations of loteprednol etabonate were below the limit of quantitation (1 ng/mL) at all time points . These finds suggest that limited, if any, systemic absorption of LE occurs . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Loteprednol etabonate is an important consideration for its dosing schedule: The terminal half-life of loteprednol etabonate as determined when administered intravenously at a dose of 5 mg/kg in the dog animal model is 2.8 hours . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Loteprednol etabonate exhibits a strong affinity for binding with plasma proteins: Strong protein binding of approximately 98% for loteprednol etabonate facilitates little pharmacodynamic action and/or adverse effects on the part of the agent in the systemic circulation . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Loteprednol etabonate from the body primarily occurs through: Following systemic administration to rats, loteprednol etabonate is eliminated primarily via the biliary/faecal route, with most of the dose eliminated in the form of the metabolite, PJ-90 . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Loteprednol etabonate is distributed throughout the body with a volume of distribution of: The only data available regarding the volume of distribution of loteprednol etabonate (LE) is the volume of distribution the agent demonstrated when administered to dogs - a value of 3.7 L/kg . It has been shown, however, that the topical ocular administration of LE distributes preferentially into the cellular components of blood . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Loteprednol etabonate is a critical factor in determining its safe and effective dosage: Loteprednol etabonate was slowly hydrolyzed in liver at clearance rates of 0.21 +/- 0.04 and 2.41 +/- 0.13 ml/h/kg in the liver and plasma, respectively . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Loteprednol etabonate exerts its therapeutic effects through: Loteprednol etabonate (LE) belongs to a unique class of corticosteroids with potent anti-inflammatory effects designed to be active at the site of action . Animal studies have shown that LE has a binding affinity to steroid receptors that is 4.3 times greater than dexamethasone . This particular class of steroids consists of bioactive molecules whose in-vivo transformation to non-toxic substances can be predicted from their chemistry and knowledge of enzymatic pathways in the body . Cortienic acid is an inactive metabolite of hydrocortisone and analogs of cortienic acid are also devoid of corticosteroid activity . Specifically, LE is an ester derivative of one of these analogs, cortienic acid etabonate . In particular, LE possesses a metabolically labile 17 beta-chloromethyl ester function which was designed in order to be hydrolyzed to an inactive carboxylic acid moiety . This inactive metabolite is more hydrophilic and is thus readily eliminated from the body . LE also exhibits good ocular permeation properties and good skin permeation properties . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Loteprednol etabonate functions by: Corticosteroids like loteprednol etabonate inhibit the inflammatory response to a variety of inciting agents and likely delay or slow healing . They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation that are commonly associated with inflammation . While glucocorticoids are known to bind to and activate the glucocorticoid receptor, the molecular mechanisms involved in glucocorticoid/glucocorticoid receptor-dependent modulation of inflammation are not clearly established . Moreover, corticosteroids are thought to inhibit prostaglandin production through several independent mechanisms . In particular, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins . It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid . Arachidonic acid is released from membrane phospholipids by phospholipase A2 . The use of LE subsequently treats post-operative inflammation and pain following ocular surgery by managing the prostaglandin release, recruitment and travel of neutrophils and macrophages, and production of other inflammatory mediators that are intrinsically associated with the physical trauma of surgery . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Loteprednol etabonate belongs to the class of organic compounds known as steroid esters. These are compounds containing a steroid moiety which bears a carboxylic acid ester group, classified under the direct parent group Steroid esters. This compound is a part of the Organic compounds, falling under the Lipids and lipid-like molecules superclass, and categorized within the Steroids and steroid derivatives class, specifically within the Steroid esters subclass.

Categories:

Loteprednol etabonate is categorized under the following therapeutic classes: Adrenal Cortex Hormones, Androstadienes, Androstanes, Androstenes, Anti-Allergic Agents, Corticosteroids, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Substrates, Fused-Ring Compounds, Immunosuppressive Agents, Steroids. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Loteprednol etabonate include:

• Water Solubility: 5 mg/mL
• Melting Point: 220-224 °C
• logP: 3.4