Loteprednol

Loteprednol etabonate
Clinical data
Trade names	Lotemax
Other names	11β,17α,Dihydroxy-21-oxa-21-chloromethylpregna-1,4-diene-3,20-dione 17α-ethylcarbonate
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Routes of; administration	Eye drops
Drug class	Corticosteroid; glucocorticoid
ATC code	S01BA14 (WHO) ;
Legal status
Legal status	US: ℞-only ;
Pharmacokinetic data
Bioavailability	None
Protein binding	95%
Metabolism	Ester hydrolysis
Metabolites	Δ1-cortienic acid and its etabonate
Onset of action	≤2 hrs (allergic conjunctivitis)
Elimination half-life	2.8 hrs
Identifiers
	show IUPAC name
CAS Number	82034-46-6 ;
PubChem CID	444025;
IUPHAR/BPS	7085;
DrugBank	DB14596 ;
ChemSpider	392049 ;
UNII	YEH1EZ96K6;
KEGG	D01689 ;
ChEBI	CHEBI:31784 ;
ChEMBL	ChEMBL1200865 ;
CompTox Dashboard (EPA)	DTXSID2046468 ;
ECHA InfoCard	100.167.120
Chemical and physical data
Formula	C24H31ClO7
Molar mass	466.96 g·mol−1
3D model (JSmol)	Interactive image;
Melting point	220.5 to 223.5 °C (428.9 to 434.3 °F)
Solubility in water	0.0005 mg/mL (20 °C)
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Loteprednol (as the ester loteprednol etabonate) is a corticosteroid used to treat inflammations of the eye. It is marketed by Bausch and Lomb as Lotemax^[1] and Loterex.

It was patented in 1980 and approved for medical use in 1998.^[2]

Medical uses[]

Applications for this drug include the reduction of inflammation after eye surgery,^[1] seasonal allergic conjunctivitis, uveitis,^[3] as well as chronic forms of keratitis (e.g. adenoviral and Thygeson's keratitis), vernal keratoconjunctivitis, pingueculitis, and episcleritis.^{[citation needed]}

Contraindications[]

As corticosteroids are immunosuppressive, loteprednol is contraindicated in patients with viral, fungal or mycobacterial infections of the eye.^[1]^[3]^[4]

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%).^[5]

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.^[1]

Pharmacology[]

Mechanism of action[]

Pharmacokinetics[]

Neither loteprednol etabonate nor its inactive metabolites Δ¹- 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.^[1]

Steroid receptor affinity was 4.3 times that of dexamethasone in animal studies.^[1]

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.^[1]^[4]^[6]

Cortisol, a naturally occurring corticosteroid, known as hydrocortisone when used as a drug
Δ¹-Cortienic acid, inactive metabolite of loteprednol
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 220.5 °C (428.9 °F) and 223.5 °C (434.3 °F). Its solubility in water is 1:2,000,000,^[4] therefore it is formulated for ophthalmic use as either an ointment, a gel, or a suspension.^[7]

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.^[8] (This is not the same as the etabonate ester.)

Hydrocortisone

Loteprednol etabonate

Chemical synthesis[]

^[9]

References[]

^ Jump up to: ^a ^b ^c ^d ^e ^f ^g Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 488. ISBN 9783527607495.
^ Jump up to: ^a ^b Loteprednol Professional Drug Facts.
^ Jump up to: ^a ^b ^c Dinnendahl V, Fricke U (2008). Arzneistoff-Profile (in German). 6 (22 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
^ "Highlights of Prescribing Information: Lotemax" (PDF). 2012.
^ Bodor N, Buchwald P (2002). "Design and development of a soft corticosteroid, loteprednol etabonate". In Schleimer RP, O'Byrne PM, Szefler SJ, Brattsand R (eds.). Inhaled Steroids in Asthma. Optimizing Effects in the Airways. Lung Biology in Health and Disease. 163. Marcel Dekker, New York. pp. 541–564.
^ "Loteprednol (Professional Patient Advice)". Retrieved October 4, 2018.
^ Pavesio CE, Decory HH (April 2008). "Treatment of ocular inflammatory conditions with loteprednol etabonate". The British Journal of Ophthalmology. 92 (4): 455–9. doi:10.1136/bjo.2007.132621. PMID 18245274. S2CID 25873047.
^ Druzgala P, Hochhaus G, Bodor N (February 1991). "Soft drugs--10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: loteprednol etabonate". The Journal of Steroid Biochemistry and Molecular Biology. 38 (2): 149–54. doi:10.1016/0960-0760(91)90120-T. PMID 2004037. S2CID 27107845.