10-Hydroxyketotifen Explained

10-Hydroxyketotifen (WR621365) is a biologically inactive metabolite of ketotifen. [1] [2] [3] Despite the mainstream scientific consensus that 10-hydroxyketotifen is a biologically inactive compound, its pharmacological properties are not very well studied outside the context of ketotifen, therefore, 10-hydroxyketotifen may still possess biological activity similarly to norketotifen, another metabolite of ketotifen.[4]

Metabolic role

See main article: article and Ketotifen. Ketotifen is an antihistamine medication which metabolizes to several compounds, including 10-hydroxyketotifen. Ketotifen, like other antihistamines,[5] [6] is mainly metabolized by the cytochrome P450 (CYP) enzymes, especially CYP3A4[7] [8] in the liver. The CYP enzymes are responsible for the oxidation and demethylation of ketotifen, producing the major metabolites norketotifen and 10-hydroxyketotifen. Norketotifen is pharmacologically active and has a similar potency as ketotifen, while 10-hydroxyketotifen is inactive. The metabolites are then conjugated with glucuronic acid or sulfate and excreted in the urine and feces.[9] [10]

The definition and measurement of biological activity of drugs can be complex: biological activity is often defined in terms of the ability of a molecule to effect a change in a biological process, which can be quantified and measured in various ways; as such, even if 10-hydroxyketotifen is currently deemed inactive, it is possible that under certain conditions or within specific biological assays, some level of activity might be observed.[4] [11]

References

  1. Web site: Gunnar AK, Wright GE, Chen JL, Maioli, AT. July 3, 2002. European Patent: optically active isomers of ketotifen and therapeutically active metabolites thereof . May 2, 2024 . May 2, 2024 . https://web.archive.org/web/20240502064104/https://data.epo.org/publication-server/rest/v1.0/publication-dates/20110720/patents/EP1218007NWB1/document.html . live .
  2. 10.1002/bms.1200100307 . Quantification of ketotifen and its metabolites in human plasma by gas chromatography mass spectrometry . 1983 . Biological Mass Spectrometry . 10 . 3 . 136–142 . 6850066 . Julien-Larose C, Guerret M, Lavene D, Kiechel JR .
  3. 10.1002/ardp.19923250502 . Direct Differential Pulse Polarographic and Adsorptive Stripping Voltammetric Assay of Ketotifen in Tablets . 1992 . Archiv der Pharmazie . 325 . 5 . 253–259 . Bersier PM, Szczepaniak W, Ren M .
  4. 10.1007/s13318-012-0080-2 . Ketotifen is an antimalarial prodrug of norketotifen with blood schizonticidal and liver-stage efficacy . 2012 . European Journal of Drug Metabolism and Pharmacokinetics . 37 . 1 . 17–22 . 22314893 . Milner E, Sousa J, Pybus B, Auschwitz J, Caridha D, Gardner S, Grauer K, Harris E, Hickman M, Kozar MP, Lee P, Leed S, Li Q, Melendez V, Moon J, Ngundam F, o'Neil M, Parriott S, Potter B, Sciotti R, Tangteung A, Dow GS .
  5. Li L, Liu R, Peng C, Chen X, Li J . Pharmacogenomics for the efficacy and side effects of antihistamines . Exp Dermatol . 31 . 7 . 993–1004 . July 2022 . 35538735 . 10.1111/exd.14602.
  6. Merk HF . Standard treatment: the role of antihistamines . J Investig Dermatol Symp Proc . 6 . 2 . 153–6 . November 2001 . 11764306 . 10.1046/j.0022-202x.2001.00032.x. free . doi .
  7. 10.1016/j.ancr.2014.11.003 . Analysis for commonly prescribed non-sedating antihistamines . 2015 . Analytical Chemistry Research . 3 . 1–12 . El-Kommos ME, El-Gizawy SM, Atia NN, Hosny NM . free .
  8. Jáuregui I, Mullol J, Bartra J, del Cuvillo A, Dávila I, Montoro J, Sastre J, Valero AL . H1 antihistamines: psychomotor performance and driving . J Investig Allergol Clin Immunol . 16 . Suppl 1. 37–44 . 2006 . 17357376.
  9. Book: https://doi.org/10.1016/B978-0-323-04404-2.10089-2 . 10.1016/B978-0-323-04404-2.10089-2 . Antihistamines . Clinical Immunology . 2008 . 1317–1329 . 978-0-323-04404-2 . Lieberman P, Hernandez-Trujillo V, Lieberman J, Frew AJ . February 14, 2024 . February 24, 2024 . https://web.archive.org/web/20240224233628/https://www.sciencedirect.com/science/article/abs/pii/B9780323044042100892?via%3Dihub . live .
  10. Web site: Center for drug evaluation and research. Application no. 21-066. February 14, 2024 . February 14, 2024 . https://web.archive.org/web/20240214190040/https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21-066_ZADITOR%200.025%25_pharmr_P1.pdf . live .
  11. 16 March 2007. 10.1007/s00769-006-0254-1 . Defining and measuring biological activity: Applying the principles of metrology . Accreditation and Quality Assurance . 12 . 6 . 283–294 . Jackson CM, Esnouf MP, Winzor DJ, Duewer DL . free .

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