Loteprednol

{{Drugbox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 407631517

| IUPAC_name = Chloromethyl 17-ethoxycarbonyloxy-11-hydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17-carboxylate

| image = Loteprednol etabonate.svg

| alt =

| drug_name = Loteprednol etabonate

| tradename = Lotemax

| Drugs.com = {{drugs.com|CONS|loteprednol}}

| MedlinePlus =

| pregnancy_AU =

| pregnancy_category =

| routes_of_administration = Eye drops

| class = Corticosteroid; glucocorticoid

| ATC_prefix = S01

| ATC_suffix = BA14

| ATC_supplemental =

| legal_AU = S4

| legal_AU_comment = {{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2014 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/resource/guidance/prescription-medicines-registration-new-chemical-entities-australia-2014 | access-date=10 April 2023}}

| legal_UK =

| legal_US = Rx-only

| legal_status =

| bioavailability = None

| protein_bound = 95%

| onset = ≤2 hrs (allergic conjunctivitis)

| metabolism = Ester hydrolysis

| metabolites = Δ¹-cortienic acid and its etabonate

| elimination_half-life = 2.8 hrs

| excretion =

| IUPHAR_ligand = 7085

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 82034-46-6

| PubChem = 444025

| DrugBank_Ref = {{drugbankcite|changed|drugbank}}

| DrugBank = DB14596

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 392049

| UNII_Ref = {{fdacite|changed|FDA}}

| UNII = YEH1EZ96K6

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D01689

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 1200865

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 31784

| synonyms = 11β,17α,Dihydroxy-21-oxa-21-chloromethylpregna-1,4-diene-3,20-dione 17α-ethylcarbonate

| C=24 | H=31 | Cl=1 | O=7

| smiles = CCOC(=O)O[C@@]1(CC[C@@H]2[C@@]1(C[C@@H]([C@H]3[C@H]2CCC4=CC(=O)C=C[C@]34C)O)C)C(=O)OCCl

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI=1S/C24H31ClO7/c1-4-30-21(29)32-24(20(28)31-13-25)10-8-17-16-6-5-14-11-15(26)7-9-22(14,2)19(16)18(27)12-23(17,24)3/h7,9,11,16-19,27H,4-6,8,10,12-13H2,1-3H3/t16-,17-,18-,19+,22-,23-,24-/m0/s1

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = DMKSVUSAATWOCU-HROMYWEYSA-N

| melting_point = 220.5

| melting_high = 223.5

| solubility = 0.0005

}}

Loteprednol (formulated as the ester loteprednol etabonate) is a topical corticosteroid used to treat inflammations of the eye. It is marketed by Bausch and Lomb as Lotemax and Loterex.

It was patented in 1980 and approved for medical use in 1998.{{cite book | vauthors = Fischer J, Ganellin CR | name-list-style = vanc |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=488 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA488 }} It is available as a generic medication.{{cite web | title=First Generic Drug Approvals 2023 | website=U.S. Food and Drug Administration (FDA) | date=30 May 2023 | url=https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/first-generic-drug-approvals | archive-url=https://web.archive.org/web/20230630003621/https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/first-generic-drug-approvals | archive-date=30 June 2023 | url-status=dead | access-date=30 June 2023}}

Medical uses

Applications for this drug include the reduction of inflammation after eye surgery, seasonal allergic conjunctivitis, uveitis, and chronic forms of keratitis - such as adenoviral, Thygeson's keratitis, vernal keratoconjunctivitis, pingueculitis, giant papillary conjunctivitis, and episcleritis.{{cite journal | vauthors = Pavesio CE, Decory HH | title = Treatment of ocular inflammatory conditions with loteprednol etabonate | journal = The British Journal of Ophthalmology | volume = 92 | issue = 4 | pages = 455–459 | date = April 2008 | pmid = 18245274 | doi = 10.1136/bjo.2007.132621 | s2cid = 25873047 }}

Contraindications

Contraindications: As corticosteroids are immunosuppressive, loteprednol is contraindicated in patients with viral, fungal or mycobacterial infections of the eye.

Adverse effects

The most common adverse effects in patients being treated with the gel formulation are anterior chamber inflammation (in 5% of people), eye pain (2%), and foreign body sensation (2%).

Interactions

Because long term use (more than 10 days) can cause increased intraocular pressure, loteprednol may interfere with the treatment of glaucoma. Following ocular administration, the drug is very slowly absorbed into the blood, therefore the blood level is limited to an extremely small concentration, and interactions with drugs taken by mouth or through any route other than topical ophthalmic are very unlikely.

Pharmacology

=Mechanism of action=

{{main article|Glucocorticoid#Mechanism of action}}Corticosteroids mediate their anti-inflammatory effects mainly through the modulation of the cytosolic glucocorticoid receptor (GR) at the genomic level. Preclinical studies demonstrated that loteprednol etabonate is highly lipophilic and has strong binding affinity to glucocorticoid receptors. After it binds to the GR in the cytoplasm, the activated corticosteroid-GR complex migrates to the nucleus, where it upregulates the expression of anti-inflammatory proteins and represses the expression of proinflammatory proteins. Corticosteroids inhibit inflammatory cytokines, chemokines, adhesion molecules, and other inflammatory mediators. They also reduce synthesis of histamine, stabilize cell membranes, and inhibit degranulation of mast cells. Recent work suggests that the activated corticosteroid-GR complex also elicits nongenomic effects, particularly the inhibition of vasodilation, vascular permeability, and migration of leukocytes. {{cite journal | vauthors = Comstock TL, Decory HH | title = Advances in corticosteroid therapy for ocular inflammation: loteprednol etabonate | journal = International Journal of Inflammation | volume = 2012 | pages = 789623 | date = 2012 | pmid = 22536546 | pmc = 3321285 | doi = 10.1155/2012/789623 | doi-access = free }}{{cite journal | vauthors = Amon M, Busin M | title = Loteprednol etabonate ophthalmic suspension 0.5 %: efficacy and safety for postoperative anti-inflammatory use | journal = International Ophthalmology | volume = 32 | issue = 5 | pages = 507–517 | date = October 2012 | pmid = 22707339 | pmc = 3459083 | doi = 10.1007/s10792-012-9589-2 }}{{cite journal | vauthors = Sheppard JD, Comstock TL, Cavet ME | title = Impact of the Topical Ophthalmic Corticosteroid Loteprednol Etabonate on Intraocular Pressure | journal = Advances in Therapy | volume = 33 | issue = 4 | pages = 532–552 | date = April 2016 | pmid = 26984315 | pmc = 4846687 | doi = 10.1007/s12325-016-0315-8 }}

=Pharmacokinetics=

Neither loteprednol etabonate nor its inactive metabolites Δ¹-cortienic acid and Δ¹-cortienic acid etabonate are detectable in the bloodstream, even after oral administration. A study with patients receiving loteprednol eye drops over 42 days showed no adrenal suppression, which would be a sign of the drug reaching the bloodstream to a clinically relevant extent.

Steroid receptor affinity was 4.3 times that of dexamethasone in animal studies.

=Retrometabolic drug design=

Loteprednol etabonate was developed using retrometabolic drug design. It is a so-called soft drug, meaning its structure was designed so that it is predictably metabolised to inactive substances. These metabolites, Δ¹-cortienic acid and its etabonate, are derivatives of cortienic acid, itself an inactive metabolite of hydrocortisone.

File:Cortisol2.svg|Cortisol, a naturally occurring corticosteroid, known as hydrocortisone when used as a drug

File:Delta1-cortienic acid skeletal.svg|Δ¹-Cortienic acid, inactive metabolite of loteprednol

File:Cortienic acid skeletal.svg|Cortienic acid, inactive metabolite of hydrocortisone

Chemistry

Loteprednol etabonate is an ester of loteprednol with etabonate (ethyl carbonate). The pure chemical compound has a melting point between {{convert|220.5|C|F}} and {{convert|223.5|C|F}}. Its solubility in water is 1:2,000,000, therefore it is formulated for ophthalmic use as either an ointment, a gel, or a suspension.

Loteprednol is a corticosteroid. The ketone side chain of classical corticosteroids such as hydrocortisone is replaced by a cleavable ester, which accounts for the rapid inactivation. (This is not the same as the etabonate ester.)

Image:Cortisol2.svg]]

Image:Loteprednol etabonate.svg

=Chemical synthesis=

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References

{{reflist|refs=

Loteprednol {{Drugs.com|ppa|loteprednol}}.

{{cite web|url=https://www.drugs.com/ppa/loteprednol.html|title=Loteprednol (Professional Patient Advice)|access-date=October 4, 2018}}

{{cite book|title=Arzneistoff-Profile| vauthors = Dinnendahl V, Fricke U |publisher=Govi Pharmazeutischer Verlag|location=Eschborn, Germany|date=2008|edition=22|volume=6|isbn=978-3-7741-9846-3|language=German}}

{{cite book|title=Austria-Codex| veditors = Haberfeld H |publisher=Österreichischer Apothekerverlag|location=Vienna|year=2015|language=German}}

{{cite journal | vauthors = Druzgala P, Hochhaus G, Bodor N | title = Soft drugs--10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: loteprednol etabonate | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 38 | issue = 2 | pages = 149–154 | date = February 1991 | pmid = 2004037 | doi = 10.1016/0960-0760(91)90120-T | s2cid = 27107845 }}

{{cite book|title=Inhaled Steroids in Asthma. Optimizing Effects in the Airways|year=2002|publisher=Marcel Dekker, New York|pages=541–564| vauthors = Bodor N, Buchwald P |chapter=Design and development of a soft corticosteroid, loteprednol etabonate | veditors = Schleimer RP, O'Byrne PM, Szefler SJ, Brattsand R | series = Lung Biology in Health and Disease | volume = 163 }}

{{cite journal | vauthors = Pavesio CE, Decory HH | title = Treatment of ocular inflammatory conditions with loteprednol etabonate | journal = The British Journal of Ophthalmology | volume = 92 | issue = 4 | pages = 455–459 | date = April 2008 | pmid = 18245274 | doi = 10.1136/bjo.2007.132621 | s2cid = 25873047 }}

{{cite web|title= Highlights of Prescribing Information: Lotemax |url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202872lbl.pdf |archive-url = https://web.archive.org/web/20140308013953/http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202872lbl.pdf |url-status = dead |archive-date = March 8, 2014 |date=2012}}

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