Identification

Name
Loteprednol etabonate
Accession Number
DB14596  (DBSALT000930)
Type
Small Molecule
Groups
Approved
Description

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 [Label]. 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 [6].

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 [4].

Structure
Thumb
Synonyms
Not Available
External IDs
CDDD 5604 / CDDD-5604 / HGP 1 / HGP-1 / KPI-121 / P 5604 / P-5604
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AlrexSuspension0.2 %OphthalmicBausch & Lomb Inc2009-06-24Not applicableCanada
AlrexSuspension / drops2 mg/1mLOphthalmicBauch & Lomb Incorporated1998-03-09Not applicableUs
AlrexSuspension / drops2 mg/1mLOphthalmicPhysicians Total Care, Inc.2002-10-17Not applicableUs
AlrexSuspension / drops2 mg/1mLOphthalmicStat Rx USA1998-03-09Not applicableUs
InveltysSuspension10 mg/1mLTopicalKala Pharmaceuticals, Inc.2018-08-22Not applicableUs
LotemaxGel5 mg/1gOphthalmicBauch & Lomb Incorporated2012-10-12Not applicableUs
LotemaxSuspension / drops5 mg/1mLOphthalmicBauch & Lomb Incorporated1998-03-09Not applicableUs
LotemaxSuspension / drops5 mg/1mLOphthalmicPhysicians Total Care, Inc.2002-10-17Not applicableUs
LotemaxSuspension0.5 %OphthalmicBausch & Lomb Inc2009-06-24Not applicableCanada
LotemaxOintment5 mg/1gOphthalmicBauch & Lomb Incorporated2011-04-15Not applicableUs
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
ZyletLoteprednol etabonate (5 mg/1mL) + Tobramycin (3 mg/1mL)Suspension / dropsOphthalmicBauch & Lomb Incorporated2004-12-14Not applicableUs
International/Other Brands
Loteflam (Cipla Pharmaceuticals Limited)
Categories
UNII
YEH1EZ96K6
CAS number
82034-46-6
Weight
Average: 466.96
Monoisotopic: 466.175831
Chemical Formula
C24H31ClO7
InChI Key
DMKSVUSAATWOCU-HROMYWEYSA-N
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
IUPAC Name
chloromethyl (1R,3aS,3bS,9aR,9bS,10S,11aS)-1-[(ethoxycarbonyl)oxy]-10-hydroxy-9a,11a-dimethyl-7-oxo-1H,2H,3H,3aH,3bH,4H,5H,7H,9aH,9bH,10H,11H,11aH-cyclopenta[a]phenanthrene-1-carboxylate
SMILES
[H][C@@]12CC[C@](OC(=O)OCC)(C(=O)OCCl)[C@@]1(C)C[C@H](O)[C@@]1([H])[C@@]2([H])CCC2=CC(=O)C=C[C@]12C

Pharmacology

Indication

A number of prescription loteprednol etabonate ophthalmic products are specifically indicated for the treatment of post-operative inflammation and pain following ocular surgery [Label].

Associated Conditions
Pharmacodynamics

Loteprednol etabonate (LE) belongs to a unique class of corticosteroids with potent anti-inflammatory effects designed to be active at the site of action [1, 5]. Animal studies have shown that LE has a binding affinity to steroid receptors that is 4.3 times greater than dexamethasone [5]. 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 [5]. Cortienic acid is an inactive metabolite of hydrocortisone and analogs of cortienic acid are also devoid of corticosteroid activity [5]. Specifically, LE is an ester derivative of one of these analogs, cortienic acid etabonate [5]. 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 [1]. This inactive metabolite is more hydrophilic and is thus readily eliminated from the body [1]. LE also exhibits good ocular permeation properties and good skin permeation properties [1].

Mechanism of action

Corticosteroids like loteprednol etabonate inhibit the inflammatory response to a variety of inciting agents and likely delay or slow healing [Label]. 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 [Label]. 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 [Label]. Moreover, corticosteroids are thought to inhibit prostaglandin production through several independent mechanisms [Label]. In particular, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins [7]. 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 [7]. Arachidonic acid is released from membrane phospholipids by phospholipase A2 [7].

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 [1].

TargetActionsOrganism
AGlucocorticoid receptor
agonist
Human
Absorption

Loteprednol etabonate (LE) demonstrates good ocular permeation properties as it is lipid soluble, allowing the agent to penetrate into cells with relative ease [Label].

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 [5]. 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 [Label]. These finds suggest that limited, if any, systemic absorption of LE occurs [5].

Volume of distribution

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 [3]. It has been shown, however, that the topical ocular administration of LE distributes preferentially into the cellular components of blood [7].

Protein binding

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 [2].

Metabolism

Loteprednol etabonate (LE) is readily and extensively metabolized to two inactive metabolites, PJ-90 (Δ1-cortienic acid) and PJ-91 (Δ1-cortienic acid etabonate) [Label]. 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 [7].

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 [2, 4]. Both metabolites are considered inactive [Label].

Route of elimination

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 [7].

Half life

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 [3].

Clearance

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 [2].

Toxicity

The most common adverse drug reactions reported during clinical trials for the medication were eye pain and posterior capsular opacification, both of which may also be the consequence of the very surgical procedures performed on the eye(s) [Label].

The agent is not absorbed systemically following topical ophthalmic administration and maternal use is not expected to result in fetal exposure to the drug [Label].

The medication is not absorbed systemically by the mother following topical ophthalmic administration, and breastfeeding is not expected to result in exposure of the child to the agent [Label].

Long-term animal studies have not been conducted to evaluate the carcinogenic potential of loteprednol etabonate. Loteprednol etabonate was not genotoxic in vitro in the Ames test, the mouse lymphoma thymidine kinase (tk) assay, or in a chromosome aberration test in human lymphocytes, or in vivo in the single dose mouse micronucleus assay [Label].

Overdose is not expected to be likely to occur after ocular administration [7].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(4R)-limoneneThe risk or severity of adverse effects can be increased when (4R)-limonene is combined with Loteprednol.
1,10-PhenanthrolineThe risk or severity of adverse effects can be increased when Loteprednol is combined with 1,10-Phenanthroline.
AceclofenacThe risk or severity of adverse effects can be increased when Aceclofenac is combined with Loteprednol.
AcemetacinThe risk or severity of adverse effects can be increased when Acemetacin is combined with Loteprednol.
Acetylsalicylic acidThe risk or severity of adverse effects can be increased when Acetylsalicylic acid is combined with Loteprednol.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Loteprednol.
AlclofenacThe risk or severity of adverse effects can be increased when Alclofenac is combined with Loteprednol.
AlclometasoneThe risk or severity of adverse effects can be increased when Alclometasone is combined with Loteprednol etabonate.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Loteprednol.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Loteprednol etabonate.
Food Interactions
Not Available

References

General References
  1. Pavesio CE, Decory HH: Treatment of ocular inflammatory conditions with loteprednol etabonate. Br J Ophthalmol. 2008 Apr;92(4):455-9. doi: 10.1136/bjo.2007.132621. Epub 2008 Feb 1. [PubMed:18245274]
  2. Samir A, Bodor N, Imai T: Identification of esterase involved in the metabolism of two corticosteroid soft drugs. Biochem Pharmacol. 2017 Mar 1;127:82-89. doi: 10.1016/j.bcp.2016.12.010. Epub 2016 Dec 22. [PubMed:28017774]
  3. Hochhaus G, Chen LS, Ratka A, Druzgala P, Howes J, Bodor N, Derendorf H: Pharmacokinetic characterization and tissue distribution of the new glucocorticoid soft drug loteprednol etabonate in rats and dogs. J Pharm Sci. 1992 Dec;81(12):1210-5. [PubMed:1491342]
  4. Druzgala P, Wu WM, Bodor N: Ocular absorption and distribution of loteprednol etabonate, a soft steroid, in rabbit eyes. Curr Eye Res. 1991 Oct;10(10):933-7. [PubMed:1959381]
  5. Electronic Medicines Compendium: Loteprednol etabonate Monograph [Link]
  6. Inveltys FDA Approval Press Release [Link]
  7. Australian Register of Therapeutic Goods: Loteprednol etabonate Product Information [File]
External Links
Human Metabolome Database
HMDB0015011
KEGG Drug
D01689
PubChem Compound
9865442
PubChem Substance
46504713
ChemSpider
392049
ChEBI
31784
ChEMBL
CHEMBL1200865
Therapeutic Targets Database
DAP001045
PharmGKB
PA164764569
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Loteprednol
AHFS Codes
  • 52:08.08 — Corticosteroids
FDA label
Download (153 KB)
MSDS
Download (22 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingTreatmentKerato Conjunctivitis Sicca1
3RecruitingTreatmentOcular inflammatory conditions1

Pharmacoeconomics

Manufacturers
  • Bausch and lomb inc
  • Pharmos corp
Packagers
  • Alchymars SPA
  • Bausch & Lomb Inc.
  • Physicians Total Care Inc.
Dosage forms
FormRouteStrength
SuspensionOphthalmic0.2 %
Suspension / dropsOphthalmic2 mg/1mL
SuspensionTopical10 mg/1mL
GelOphthalmic5 mg/1g
OintmentOphthalmic5 mg/1g
SuspensionOphthalmic0.5 %
Suspension / dropsOphthalmic5 mg/1mL
GelOphthalmic0.5 %
OintmentOphthalmic0.5 %
Suspension / dropsOphthalmic
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5540930No1993-10-252013-10-25Us
US4996335No1995-03-092012-03-09Us
CA2174550No2002-10-012014-10-21Canada
US5800807No1997-01-292017-01-29Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)220-224 °CNot Available
water solubility5 mg/mLNot Available
logP3.4Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00693 mg/mLALOGPS
logP3.08ALOGPS
logP3.94ChemAxon
logS-4.8ALOGPS
pKa (Strongest Acidic)14.88ChemAxon
pKa (Strongest Basic)-2.9ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area99.13 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity118.17 m3·mol-1ChemAxon
Polarizability48.43 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9884
Blood Brain Barrier+0.9294
Caco-2 permeable+0.5426
P-glycoprotein substrateSubstrate0.7489
P-glycoprotein inhibitor INon-inhibitor0.6379
P-glycoprotein inhibitor IINon-inhibitor0.6419
Renal organic cation transporterNon-inhibitor0.7633
CYP450 2C9 substrateNon-substrate0.862
CYP450 2D6 substrateNon-substrate0.914
CYP450 3A4 substrateSubstrate0.794
CYP450 1A2 substrateNon-inhibitor0.8987
CYP450 2C9 inhibitorNon-inhibitor0.8866
CYP450 2D6 inhibitorNon-inhibitor0.872
CYP450 2C19 inhibitorNon-inhibitor0.9233
CYP450 3A4 inhibitorNon-inhibitor0.5687
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8468
Ames testNon AMES toxic0.8574
CarcinogenicityNon-carcinogens0.9436
BiodegradationNot ready biodegradable0.9614
Rat acute toxicity2.2305 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9647
hERG inhibition (predictor II)Non-inhibitor0.5773
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-06di-0794200000-c3979b4c8c9d5097df0e

Taxonomy

Description
This compound 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.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Steroid esters
Direct Parent
Steroid esters
Alternative Parents
Androgens and derivatives / 3-oxo delta-1,4-steroids / 11-beta-hydroxysteroids / Delta-1,4-steroids / Carbonic acid diesters / Secondary alcohols / Cyclic ketones / Cyclic alcohols and derivatives / Carboxylic acid esters / Monocarboxylic acids and derivatives
show 4 more
Substituents
Steroid ester / Androgen-skeleton / Androstane-skeleton / 3-oxo-delta-1,4-steroid / 3-oxosteroid / 11-hydroxysteroid / 11-beta-hydroxysteroid / Oxosteroid / Hydroxysteroid / Delta-1,4-steroid
show 20 more
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
organochlorine compound, 11beta-hydroxy steroid, steroid ester, etabonate ester, 3-oxo-Delta(1),Delta(4)-steroid, steroid acid ester (CHEBI:31784)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Zinc ion binding
Specific Function
Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modula...
Gene Name
NR3C1
Uniprot ID
P04150
Uniprot Name
Glucocorticoid receptor
Molecular Weight
85658.57 Da
References
  1. Druzgala P, Hochhaus G, Bodor N: Soft drugs--10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: loteprednol etabonate. J Steroid Biochem Mol Biol. 1991 Feb;38(2):149-54. [PubMed:2004037]
  2. Bodor N, Buchwald P: Corticosteroid design for the treatment of asthma: structural insights and the therapeutic potential of soft corticosteroids. Curr Pharm Des. 2006;12(25):3241-60. [PubMed:17020532]
  3. Szelenyi I, Hochhaus G, Heer S, Kusters S, Marx D, Poppe H, Engel J: Loteprednol etabonate: a soft steroid for the treatment of allergic diseases of the airways. Drugs Today (Barc). 2000 May;36(5):313-20. [PubMed:12861354]
  4. Samudre SS, Lattanzio FA Jr, Williams PB, Sheppard JD Jr: Comparison of topical steroids for acute anterior uveitis. J Ocul Pharmacol Ther. 2004 Dec;20(6):533-47. [PubMed:15684812]
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. NCI/NIH [Link]
  2. Electronic Medicines Compendium: Loteprednol etabonate Monograph [Link]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Substrate
General Function
Protein homodimerization activity
Specific Function
Hydrolyzes the toxic metabolites of a variety of organophosphorus insecticides. Capable of hydrolyzing a broad spectrum of organophosphate substrates and lactones, and a number of aromatic carboxyl...
Gene Name
PON1
Uniprot ID
P27169
Uniprot Name
Serum paraoxonase/arylesterase 1
Molecular Weight
39730.99 Da
References
  1. Samir A, Bodor N, Imai T: Identification of esterase involved in the metabolism of two corticosteroid soft drugs. Biochem Pharmacol. 2017 Mar 1;127:82-89. doi: 10.1016/j.bcp.2016.12.010. Epub 2016 Dec 22. [PubMed:28017774]

Drug created on June 13, 2005 07:24 / Updated on September 21, 2018 00:06