
Loading Pathway...
Error: Pathway image not found.
Hide
Pathway Description
Loteprednol etabonate Action Pathway
Homo sapiens
Drug Action Pathway
Created: 2023-06-08
Last Updated: 2023-10-25
Loteprednol etabonate (LE), also known as Lotemax, is a corticosteroid used to treat allergic conjunctivitis as well as inflammation and pain after ocular surgery. It is used in ophthalmic solutions for the treatment of steroid-responsive inflammatory conditions of the eye. LE was purposefully engineered to be a 'soft drug', which means that it is active locally at the site of administration and then it is rapidly metabolized to its inactive components. This kind of action minimizes the chance of adverse effects. As LE is a glucocorticoid, its mechanism of action is that of the glucocorticoid response element (GRE) influencing COX-2/prostaglandin G/H synthase 2 suppression and lipocortin/annexin induction. By binding to the glucocorticoid receptor, it influences transcription factors AP-1 and NF-kB to block the transcription of COX-2/prostaglandin G/H synthase 2 which reduces the amount of prostanoids being produced from arachidonic acid. Prostanoids such as PGI2 and thromboxane A2 influence the effects of inflammation through vasoconstriction/dilation, pain sensitivity, and platelet aggregation. This molecule also affects the promoter of annexin-1, an important inflammatory protein as it affects leukocytes and blocks phospholipase A2 which reduces the amount of arachidonic acid being cleaved from the phospholipid bilayer. Reducing the amount of arachidonic acid formed further decreases the concentrations of prostanoids mentioned calming inflammation.
References
Loteprednol etabonate Pathway References
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
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
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. doi: 10.1002/jps.2600811217.
Pubmed: 1491342
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. doi: 10.3109/02713689109020329.
Pubmed: 1959381
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. doi: 10.1016/0960-0760(91)90120-t.
Pubmed: 2004037
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. doi: 10.2174/138161206778194132.
Pubmed: 17020532
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. doi: 10.1089/jop.2004.20.533.
Pubmed: 15684812
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. doi: 10.1093/nar/30.1.412.
Pubmed: 11752352
Kim S. W, Ko J, Kim J. H, Choi E. C, Na D. S. Differential effects of annexins I, II, III, and V on cytosolic phospholipase A2 activity: specific interaction model. FEBS Letters 489: 243-248, 2001.
Necela B. M, Cidlowski J. A. Mechanisms of Glucocorticoid Receptor Action in Noninflammatory and Inflammatory Cells. American Thoracic Society 1:239-246, 2004.
Lim J. W, Kim H, Kim K. H. Nuclear Factor-kB Regulates Cyclooxygenase-2 Expression and Cell Proliferation in Human Gastric Cancer Cells. Laboratory Investigation 81 (3): 349- 360, 2001.
Oeckinghaus A, Ghosh S. The NF-kB Family of Transcription Factors and Its Regulation. Cold Spring Harb Perspect Biol 1(4): a000034, 2009.
Yokoyama C, Tanabe T: Cloning of human gene encoding prostaglandin endoperoxide synthase and primary structure of the enzyme. Biochem Biophys Res Commun. 1989 Dec 15;165(2):888-94. doi: 10.1016/s0006-291x(89)80049-x.
Pubmed: 2512924
Funk CD, Funk LB, Kennedy ME, Pong AS, Fitzgerald GA: Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment. FASEB J. 1991 Jun;5(9):2304-12.
Pubmed: 1907252
Takahashi Y, Ueda N, Yoshimoto T, Yamamoto S, Yokoyama C, Miyata A, Tanabe T, Fuse I, Hattori A, Shibata A: Immunoaffinity purification and cDNA cloning of human platelet prostaglandin endoperoxide synthase (cyclooxygenase). Biochem Biophys Res Commun. 1992 Jan 31;182(2):433-8. doi: 10.1016/0006-291x(92)91750-k.
Pubmed: 1734857
Kosaka T, Miyata A, Ihara H, Hara S, Sugimoto T, Takeda O, Takahashi E, Tanabe T: Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2. Eur J Biochem. 1994 May 1;221(3):889-97. doi: 10.1111/j.1432-1033.1994.tb18804.x.
Pubmed: 8181472
Jones DA, Carlton DP, McIntyre TM, Zimmerman GA, Prescott SM: Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines. J Biol Chem. 1993 Apr 25;268(12):9049-54.
Pubmed: 8473346
Hla T, Neilson K: Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7384-8. doi: 10.1073/pnas.89.16.7384.
Pubmed: 1380156
Yokoyama C, Miyata A, Ihara H, Ullrich V, Tanabe T: Molecular cloning of human platelet thromboxane A synthase. Biochem Biophys Res Commun. 1991 Aug 15;178(3):1479-84. doi: 10.1016/0006-291x(91)91060-p.
Pubmed: 1714723
Ohashi K, Ruan KH, Kulmacz RJ, Wu KK, Wang LH: Primary structure of human thromboxane synthase determined from the cDNA sequence. J Biol Chem. 1992 Jan 15;267(2):789-93.
Pubmed: 1730669
Miyata A, Yokoyama C, Ihara H, Bandoh S, Takeda O, Takahashi E, Tanabe T: Characterization of the human gene (TBXAS1) encoding thromboxane synthase. Eur J Biochem. 1994 Sep 1;224(2):273-9. doi: 10.1111/j.1432-1033.1994.00273.x.
Pubmed: 7925341
Miyata A, Hara S, Yokoyama C, Inoue H, Ullrich V, Tanabe T: Molecular cloning and expression of human prostacyclin synthase. Biochem Biophys Res Commun. 1994 May 16;200(3):1728-34. doi: 10.1006/bbrc.1994.1652.
Pubmed: 8185632
Chevalier D, Cauffiez C, Bernard C, Lo-Guidice JM, Allorge D, Fazio F, Ferrari N, Libersa C, Lhermitte M, D'Halluin JC, Broly F: Characterization of new mutations in the coding sequence and 5'-untranslated region of the human prostacylcin synthase gene (CYP8A1). Hum Genet. 2001 Feb;108(2):148-55. doi: 10.1007/s004390000444.
Pubmed: 11281454
Deloukas P, Matthews LH, Ashurst J, Burton J, Gilbert JG, Jones M, Stavrides G, Almeida JP, Babbage AK, Bagguley CL, Bailey J, Barlow KF, Bates KN, Beard LM, Beare DM, Beasley OP, Bird CP, Blakey SE, Bridgeman AM, Brown AJ, Buck D, Burrill W, Butler AP, Carder C, Carter NP, Chapman JC, Clamp M, Clark G, Clark LN, Clark SY, Clee CM, Clegg S, Cobley VE, Collier RE, Connor R, Corby NR, Coulson A, Coville GJ, Deadman R, Dhami P, Dunn M, Ellington AG, Frankland JA, Fraser A, French L, Garner P, Grafham DV, Griffiths C, Griffiths MN, Gwilliam R, Hall RE, Hammond S, Harley JL, Heath PD, Ho S, Holden JL, Howden PJ, Huckle E, Hunt AR, Hunt SE, Jekosch K, Johnson CM, Johnson D, Kay MP, Kimberley AM, King A, Knights A, Laird GK, Lawlor S, Lehvaslaiho MH, Leversha M, Lloyd C, Lloyd DM, Lovell JD, Marsh VL, Martin SL, McConnachie LJ, McLay K, McMurray AA, Milne S, Mistry D, Moore MJ, Mullikin JC, Nickerson T, Oliver K, Parker A, Patel R, Pearce TA, Peck AI, Phillimore BJ, Prathalingam SR, Plumb RW, Ramsay H, Rice CM, Ross MT, Scott CE, Sehra HK, Shownkeen R, Sims S, Skuce CD, Smith ML, Soderlund C, Steward CA, Sulston JE, Swann M, Sycamore N, Taylor R, Tee L, Thomas DW, Thorpe A, Tracey A, Tromans AC, Vaudin M, Wall M, Wallis JM, Whitehead SL, Whittaker P, Willey DL, Williams L, Williams SA, Wilming L, Wray PW, Hubbard T, Durbin RM, Bentley DR, Beck S, Rogers J: The DNA sequence and comparative analysis of human chromosome 20. Nature. 2001 Dec 20-27;414(6866):865-71. doi: 10.1038/414865a.
Pubmed: 11780052
Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B: A model for p53-induced apoptosis. Nature. 1997 Sep 18;389(6648):300-5. doi: 10.1038/38525.
Pubmed: 9305847
Jakobsson PJ, Thoren S, Morgenstern R, Samuelsson B: Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7220-5. doi: 10.1073/pnas.96.13.7220.
Pubmed: 10377395
Forsberg L, Leeb L, Thoren S, Morgenstern R, Jakobsson P: Human glutathione dependent prostaglandin E synthase: gene structure and regulation. FEBS Lett. 2000 Apr 7;471(1):78-82. doi: 10.1016/s0014-5793(00)01367-3.
Pubmed: 10760517
Nagata A, Suzuki Y, Igarashi M, Eguchi N, Toh H, Urade Y, Hayaishi O: Human brain prostaglandin D synthase has been evolutionarily differentiated from lipophilic-ligand carrier proteins. Proc Natl Acad Sci U S A. 1991 May 1;88(9):4020-4. doi: 10.1073/pnas.88.9.4020.
Pubmed: 1902577
White DM, Mikol DD, Espinosa R, Weimer B, Le Beau MM, Stefansson K: Structure and chromosomal localization of the human gene for a brain form of prostaglandin D2 synthase. J Biol Chem. 1992 Nov 15;267(32):23202-8.
Pubmed: 1385416
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
Penning TM, Burczynski ME, Jez JM, Lin HK, Ma H, Moore M, Ratnam K, Palackal N: Structure-function aspects and inhibitor design of type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3). Mol Cell Endocrinol. 2001 Jan 22;171(1-2):137-49. doi: 10.1016/s0303-7207(00)00426-3.
Pubmed: 11165022
Lovering AL, Ride JP, Bunce CM, Desmond JC, Cummings SM, White SA: Crystal structures of prostaglandin D(2) 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin. Cancer Res. 2004 Mar 1;64(5):1802-10.
Pubmed: 14996743
Qin KN, New MI, Cheng KC: Molecular cloning of multiple cDNAs encoding human enzymes structurally related to 3 alpha-hydroxysteroid dehydrogenase. J Steroid Biochem Mol Biol. 1993 Dec;46(6):673-9.
Pubmed: 8274401
Highlighted elements will appear in red.
Highlight Compounds
Highlight Proteins
Enter relative concentration values (without units). Elements will be highlighted in a color gradient where red = lowest concentration and green = highest concentration. For the best results, view the pathway in Black and White.
Visualize Compound Data
Visualize Protein Data
Downloads
Settings