Loteprednol

Loteprednol etabonate
Clinical data
Trade names	Lotemax
Other names	HGP 1
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Routes of; administration	Eye drops
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
	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;
CAS Number	82034-46-6 ;
PubChem CID	444025;
IUPHAR/BPS	7085;
DrugBank	DB00873 ;
ChemSpider	392049 ;
UNII	Z8CBU6KR16;
KEGG	D01689 ;
ChEBI	CHEBI:31784;
ChEMBL	ChEMBL1201389 ;
CompTox Dashboard (EPA)	DTXSID2046468 ;
ECHA InfoCard	100.167.120
Chemical and physical data
Formula	C24H31ClO7
Molar mass	466.951 g/mol 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)
	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;
	InChI InChI=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; Key:DMKSVUSAATWOCU-HROMYWEYSA-N;
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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]

Medical uses

Applications for this drug include the reduction of inflammation after eye surgery,^[1] seasonal allergic conjunctivitis, uveitis,^[2] 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]^[2]^[3]

Adverse effects

Common adverse effects include foreign body sensation in the eye, dry eye and epiphora (overflow of tears), chemosis (swelling of the conjunctiva), headache, and itching. Increased intraocular pressure, a side effect typical of corticosteroids, occurs in about 2% of patients^[1]^[2] (compared to 7% under prednisolone acetate and 0.5% under placebo).^[3]

Interactions

The effect of drugs lowering intraocular pressure may be reduced. Loteprednol is not detectable in the bloodstream; so interactions with systemic drugs are highly unlikely.^[1]

Pharmacology

Mechanism of action

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.^[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]^[3]^[4]

Δ¹-Cortienic acid, inactive metabolite of loteprednol
Cortienic acid, inactive metabolite of hydrocortisone
Hydrocortisone, the "parent compound" of corticosteroids

Chemistry

Loteprednol etabonate is an ester of loteprednol with etabonate (ethyl carbonate), with 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.^[3] The ketone in the side chain of classical corticosteroids such as hydrocortisone is replaced by a cleavable ester, which accounts for the rapid inactivation.^[5] (This is not the same as the etabonate ester.)

Chemical synthesis

^[6]

References

^ ^a ^b ^c ^d ^e ^f ^g ^h Haberfeld, H., ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
^ ^a ^b ^c Loteprednol Professional Drug Facts.
^ ^a ^b ^c ^d Dinnendahl, V.; Fricke, U., eds. (2008). Arzneistoff-Profile (in German). Vol. 6 (22 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
^ Bodor, N.; Buchwald, P. (2002). "Design and development of a soft corticosteroid, loteprednol etabonate". In Schleimer, R.P.; O'Byrne, P.M.; Szefler, S.J.; Brattsand, R. (eds.). Inhaled Steroids in Asthma. Optimizing Effects in the Airways. Marcel Dekker, New York. pp. 541–564. {{cite book}}: |work= ignored (help)
^ Pavesio, C.E.; Decory, H.H. (2008). "Treatment of ocular inflammatory conditions with loteprednol etabonate". Br J Ophthalmol. 92 (4): 455–459. doi:10.1136/bjo.2007.132621. PMID 18245274.
^ Druzgala, P.; Hochhaus, G.; Bodor, N. (1991). "Soft drugs—10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: Loteprednol etabonate". J. Steroid Biochem. Mol. Biol. 38 (2): 149–54. doi:10.1016/0960-0760(91)90120-T. PMID 2004037.{{cite journal}}: CS1 maint: multiple names: authors list (link)