Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Zileuton: Difference between pages

{{Short description|Chemical compound}}

| verifiedrevid = 470635835

| IUPAC_name = ''N''-[1-(1-benzothien-2-yl)ethyl]-''N''-hydroxyurea

| image = Zileuton.svg

| image2 = Zileuton ball-and-stick model.png

| chirality = [[Racemic mixture]]

| pronounce = {{IPAc-en|z|aɪ|ˈ|l|uː|t|ə|n}}<br />{{respell|zy|LOO|tən}}

| DailyMedID = Zileuton

| licence_US = Zileuton

| IUPHAR_ligand = 5297

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| C=11 | H=12 | N=2 | O=2 | S=1

[[File:Zyflo.JPG|thumb|300px|Abbott Laboratories stock bottle of Zyflo (zileuton) 600 mg tablets (manufactured 1997). Also shown are Zyflo tablets, with one tab broken. Tablets are branded with the Abbott "a" logo and "ZL".]]

'''Zileuton''' (trade name Zyflo) is an orally active inhibitor of [[5-lipoxygenase]], and thus inhibits [[leukotrienes]] (LTB₄, LTC₄, LTD₄, and LTE₄) formation, used for the maintenance treatment of [[asthma]]. Zileuton was introduced in 1996 by [[Abbott Laboratories]] and is now marketed in two formulations by Cornerstone Therapeutics Inc. under the brand names Zyflo and Zyflo CR. The original immediate-release formulation, Zyflo, is taken four times per day. The extended-release formulation, Zyflo CR, is taken twice daily.

Although the 600&nbsp;mg immediate release tablet (Zyflo)<!--Follow this link and click Zyflo: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Zileuton&SearchType=BasicSearch --> and extended release formulation of zileuton are still available (Zyflo CR), the 300&nbsp;mg immediate release tablet was withdrawn from the U.S. market on February 12, 2008.<ref name="mayocliniczileuton">{{cite web | url = http://www.mayoclinic.com/health/drug-information/DR601451 | title = Zileuton (Oral Route) | work = MayoClinic }}</ref><ref name="drugscomzileuton">{{cite web | url = https://www.drugs.com/cons/zyflo.html | title = Zyflo consumer information | work = Drugs.com }}</ref>

==Pharmacotherapy==

===Indications and dosing===

Zileuton is indicated for the [[prophylaxis]] and chronic treatment of asthma in adults and children 12 years of age and older. Zileuton is not indicated for use in the reversal of [[bronchospasm]] in acute asthma attacks. Therapy with zileuton can be continued during acute exacerbations of asthma.

The recommended dose of Zyflo is one 600&nbsp;mg tablet, four times per day. The tablets may be split in half to make them easier to swallow. The recommended dose of Zyflo CR is two 600&nbsp;mg extended-release tablets twice daily, within one hour after morning and evening meals, for a daily dose of 2400&nbsp;mg. Do not split Zyflo CR tablets in half.

Related compounds include [[montelukast]] (Singulair) and [[zafirlukast]] (Accolate). These two compounds are leukotriene receptor antagonists which block the action of specific leukotrienes, while zileuton inhibits leukotriene formation.

;Research

Research on mice suggests that Zileuton used alone or in combination with [[imatinib]] may inhibit [[chronic myeloid leukemia]] (CML).<ref>{{cite web | work = ScienceDaily | date = 8 June 2009 | url = https://www.sciencedaily.com/releases/2009/06/090607153256.htm | title = Lethal Cancer Knocked Down By One-two Drug Punch }}</ref> It has also been researched in a mouse model of [[dementia]].<ref name="pmid29881943">{{cite journal | vauthors = Giannopoulos PF, Chiu J, Praticò D | title = Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 Kinase Pathway | journal = Molecular Neurobiology | volume = 56 | issue = 2 | pages = 1211–1220 | date = February 2019 | pmid = 29881943 | doi = 10.1007/s12035-018-1124-7 | s2cid = 46956142 }}</ref>

===Contraindications and warnings===

The most serious side effect of Zyflo and Zyflo CR is a potential elevation of liver enzymes (in 2% of patients). Therefore, zileuton is contraindicated in patients with active liver disease or persistent hepatic function enzymes elevations greater than three times the upper limit of normal. Hepatic function should be assessed prior to initiating Zyflo CR, monthly for the first 3 months, every 2–3 months for the remainder of the first year, and periodically thereafter.

Neuropsychiatric events, including sleep disorders and behavioral changes, may occur with Zyflo and Zyflo CR. Patients should be instructed to notify their healthcare provider if neuropsychiatric events occur while using Zyflo or Zyflo CR.

Zileuton is a weak inhibitor of [[CYP1A2]]<ref>{{cite journal | vauthors = Lu P, Schrag ML, Slaughter DE, Raab CE, Shou M, Rodrigues AD | title = Mechanism-based inhibition of human liver microsomal cytochrome P450 1A2 by zileuton, a 5-lipoxygenase inhibitor | journal = Drug Metabolism and Disposition | volume = 31 | issue = 11 | pages = 1352–1360 | date = November 2003 | pmid = 14570767 | doi = 10.1124/dmd.31.11.1352 | s2cid = 22714315 }}</ref> and thus has three clinically important drug interactions, which include increasing [[theophylline]], and [[propranolol]] levels. It has been shown to lower theophylline clearance significantly, doubling the AUC and prolonging half-life by nearly 25%. Because of theophylline's relation to [[caffeine]] (both being a [[methylxanthine]], and theophylline being a metabolite of caffeine), caffeine's metabolism and clearance may also be reduced, but there are no drug interaction studies between zileuton and caffeine.<ref>Cafcit (caffeine citrate) package insert. Evansville, IN: Mead Johnson & Company; 2003 May.</ref> The ''R''-isomer of warfarin metabolism and clearance is mainly affected by zileuton, while the ''S''-isomer is not (because of metabolism via different enzymes). This can lead to an increase in [[prothrombin]] time.<ref>Zyflo Filmtab (zileuton) package insert. Chicago, IL: Abbott Laboratories; 1998 Mar.</ref>

==Chemistry==

Zileuton is an active oral inhibitor of the enzyme [[5-lipoxygenase]], which forms [[leukotrienes]], [[5-hydroxyeicosatetraenoic acid]], and [[5-oxo-eicosatetraenoic acid]] from [[arachidonic acid]]. The chemical name of zileuton is (±)-1-(1-Benzo[b]thien-2-ylethyl)-l-hydroxyurea.<ref name="KrutetskayaMilenina2016">{{cite journal | vauthors = Krutetskaya ZI, Milenina LS, Naumova AA, Antonov VG, Nozdrachev AD | title = 5-Lipoxygenase inhibitor zileuton inhibits Ca(2+)-responses induced by glutoxim and molixan in macrophages | journal = Doklady. Biochemistry and Biophysics | volume = 469 | issue = 1 | pages = 302–304 | date = July 2016 | pmid = 27599517 | doi = 10.1134/S1607672916040177 | s2cid = 3132863 }}</ref>

The molecular formula of zileuton is C₁₁H₁₂N₂O₂S with a molecular weight of 236.29. The formulation from the manufacturer is a [[racemic mixture]] of ''R''(+) and ''S''(-) enantiomers.<ref name="zyfloarticle">{{cite web | url = http://www.rxlist.com/zyflo-drug.htm | title = Zyflo Drug Information | work = rxlist }}</ref>

==Pharmacokinetics==

Following oral administration zileuton is rapidly absorbed with a mean time to peak [[blood serum]] concentration of 1.7 hours and an average half-life elimination of 2.5 hours. [[Blood plasma]] concentrations are proportional to dose, whereas the absolute [[bioavailability]] is unknown.

The apparent [[volume of distribution]] of zileuton is approximately 1.2 L/kg. Zileuton is 93% bound to plasma proteins, primarily to [[albumin]], with minor binding to [[alpha-1-acid glycoprotein]].

Elimination of zileuton is primarily through metabolites in the urine (~95%) with the feces accounting for the next largest amount (~2%). The drug is metabolized by the cytochrome P450 enzymes: CYP1A2, 2C9, and 3A4.<ref name="zyfloarticle" />

==Adverse effects==

The most common adverse reactions reported by patients treated with Zyflo CR were [[sinusitis]] (6.5%), [[nausea]] (5%), and pharyngolaryngeal pain (5%) vs. placebo, 4%, 1.5%, and 4% respectively.

== Interactions ==

===Drug interactions===

Zileuton is a minor substrate of CYP1A2, 2C8/9, 3A4, and a weak inhibitor of CYP 1A2. The drug has been shown to increase the serum concentration or effects of [[theophylline]], [[propranolol]], and [[warfarin]], although significant increase in prothrombin time is not obvious. It is advised that the doses of each medication be monitored and/or reduced accordingly.

===Other interactions===

The avoidance of [[alcohol (drug)|alcohol]] is recommended due to increased risk of CNS depression as well as an increased risk of liver toxicity. In addition, the herbal supplement [[St. John's wort]] may decrease the serum levels of zileuton.<ref name="zyflomonograph">{{cite web | title = Zileuton monograph | work = Lexi-Comp Online, Lexi-Drugs Online | publisher = Lexi-Comp Inc. | location = Hudson, OH | url = http://crlonline.com/crlonline |access-date= September 14, 2008 |url-status=dead |archive-url=https://web.archive.org/web/20041116092554/http://www.crlonline.com/crlonline |archive-date= 16 November 2004 }}</ref>

==Overdose/toxicology==

===Symptoms===

Human experience of acute overdose with zileuton is limited. A patient in a clinical study took between 6.6 and 9.0&nbsp;grams of zileuton immediate-release tablets in a single dose. Vomiting was inducted and the patient recovered without [[sequelae]]. Zileuton is not removed by dialysis.

The oral minimum lethal doses in mice and rats were 500-4000 and 300–1000&nbsp;mg/kg, respectively (providing greater than 3 and 9 times the systemic exposure (AUC) achieved at the maximum recommended human daily oral dose, respectively). In dogs, at an oral dose of 1000&nbsp;mg/kg (providing in excess of 12 times the systemic exposure (AUC) achieved at the maximum recommended human daily oral dose) no deaths occurred but nephritis was reported.

===Treatment===

Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted as required. If indicated, elimination of unabsorbed drug should be achieved by [[emesis]] or [[gastric lavage]]; usual precautions should be observed to maintain the airway. A Certified Poison Control Center should be consulted for up-to-date information on management of overdose with Zyflo CR.

== See also ==

* [[Lipoxygenase inhibitor]]

== References ==

{{Reflist|2}}

== External links ==

* {{cite web | url = http://www.zyflo.com/ | title = Zyflo | work = manufacturer's website | archive-url = https://web.archive.org/web/20060622115551/http://www.zyflo.com/ | archive-date = 2006-06-22 }}

* {{cite web | url = http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=4821 | title = Zyflo (patient information) | work = DailyMed | publisher = U.S. National Library of Medicine }}

* {{cite web | url = https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm | archive-url = https://web.archive.org/web/20120106044649/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm | archive-date = 6 January 2012 | title = Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers | publisher = U.S. Food and Drug Administration }}

{{Asthma and copd rx}}

{{Leukotrienergics}}

[[Category:CYP1A2 inhibitors]]

[[Category:Leukotriene pathway inhibitors]]

[[Category:Benzothiophenes]]

[[Category:Drugs developed by AbbVie]]