Chemistry:Tazarotene

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Short description: Topical retinoid drug
Tazarotene
Skeletal formula of tazarotene
Space-filling model of the tazarotene molecule
Clinical data
Trade namesTazorac, Avage, Zorac, Fabior, Arazlo
AHFS/Drugs.comMonograph
Pregnancy
category
  • X (U.S.)
Routes of
administration		Topical
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding>99%
Elimination half-life19 Hours
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC21H21NO2S
Molar mass351.46 g·mol−1
3D model (JSmol)
  (verify)

Tazarotene, sold under the brand name Tazorac, among others, is a third-generation prescription topical retinoid.[1][2] It is primarily used for the treatment of plaque psoriasis and acne.[3] Tazarotene is also used as a therapeutic for photoaged and photodamaged skin.[3] It is a member of the acetylenic class of retinoids.[3]

Tazarotene was approved for medical use in 1997[4] and is available as a generic medication.[5][6]

Medical uses

Tazarotene is most commonly used topically to treat acne vulgaris and psoriasis.[3] Like other topical retinoids, such as tretinoin and adapalene, tazarotene can be combined with benzoyl peroxide or an oral antibiotic, such as clindamycin or dapsone, for the treatment of acne.[7] This results in increased efficacy compared to tazarotene monotherapy.[7] For psoriasis, a combination therapy of tazarotene and a mid- to high-potency corticosteroid is more effective than either treatment alone.[8]

Tazarotene can also be used for the treatment of photodamaged skin. It can reduce the clinical and histological signs of photodamaged skin.[9] The therapy is more effective when used with the daily application of sunscreen.[10]

Pregnancy

Before 2015, tazarotene was considered a Category X drug (meaning its use was contraindicated during pregnancy) according to Food and Drug Administration (FDA) guidelines, despite demonstrating similar plasma retinoid levels as adapalene and tretinoin, which were classified as Category C drugs.[11] Under the FDA's updated Pregnancy and Lactation Labeling Rule which eliminated the lettered pregnancy categories and came into effect in 2015, tazarotene was determined to be contraindicated in pregnancy.[11] Because of the lack of pregnancy outcomes data for the drug, the determination was based on the teratogenic effects observed in rat and rabbit studies.[4][11]

Contraindications

Tazarotene is contraindicated for use in patients who are known to be or suspected of being pregnant. Tazarotene is a known teratogen.[3] It is also contraindicated in patients with a known hypersensitivity to any ingredient in the specific pharmaceutical formulation.[3]

Adverse effects

Adverse effects for tazarotene include skin irritation, such as redness, itchiness, and burning. In patients with psoriasis, these adverse effects can be mitigated by a combined treatment with either mometasone furoate or fluocinonide.[8] These effects tend to be mild to moderate, and increase in intensity as tazarotene concentration increases.[12]

Pharmacology

Mechanism of action

Tazarotene is selective for two types of retinoic acid receptors, RAR-γ and RAR-β.[13] Like all retinoids, it affects the ability of keratinocytes in the epidermis to proliferate and differentiate.[13] It does so by upregulating filaggrin expression and downregulating the expression of keratinocyte transglutaminase, ornithine decarboxylase, involucrin, epidermal growth factor receptor, and various keratins.[14]

Pharmacokinetics

More than 99% of tazarotenic acid, the active metabolite of tazarotene, in the blood binds to plasma proteins (the most predominant being albumin).[15] The volume of distribution (VD) for tazarotene is 26.1 L/kg and the VD for tazarotenic acid is 1.97 L/kg.[15] Tazarotene is excreted from the body via feces and urine equally,[8] and it has an elimination half-life of 16[16] to 18 hours.[17]

Synthesis

Acetylenic retinoid prodrug converted to the active metabolite, tazarotenic acid, with selective affinity for retinoic acid receptors RARβ and RARγ.

Tazarotene synthesis:[18]

The formation of the ring system involves first alkylation of the anion from thiophenol with dimethylallyl bromide (1) to give the thioether (2). Friedel-Crafts cyclization of the olefin with the equivalent of PPA then gives the thiopyran (3). Acylation with acetyl chloride in the presence of aluminium chloride gives the methyl ketone (4). Reaction of the enolate of that ketone with diethyl chlorophosphate gives the enol phosphate 5 as a transient intermediate. This eliminates diethyl phosphite in the presence of excess base to give the corresponding acetylene 6. The anion from the reaction of the acetylene with base is then used to displace chlorine from Ethyl 6-chloronicotinate (7). This reaction affords the coupling product tazarotene (8).

References

  1. ↑ "Topical retinoids in acne--an evidence-based overview". J Dtsch Dermatol Ges 6 (12): 1023–31. December 2008. doi:10.1111/j.1610-0387.2008.06741.x. PMID 18479477. 
  2. ↑ American Society of Health-System Pharmacists, Inc.. "Tazarotene". MedlinePlus Drug Information. U.S. National Library of Medicine. https://medlineplus.gov/druginfo/meds/a616052.html. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 "Tazarotene Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/tazarotene.html. 
  4. ↑ 4.0 4.1 "Arazlo (tazarotene) [package insert"]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211882s000lbl.pdf. 
  5. ↑ "2022 First Generic Drug Approvals". 3 March 2023. https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/2022-first-generic-drug-approvals. 
  6. ↑ "Competitive Generic Therapy Approvals". 29 June 2023. https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals. 
  7. ↑ 7.0 7.1 "Topical Retinoids in Acne Vulgaris: A Systematic Review". Am J Clin Dermatol 20 (3): 345–365. June 2019. doi:10.1007/s40257-019-00423-z. PMID 30674002. 
  8. ↑ 8.0 8.1 8.2 "Tazarotene". Drugs 55 (5): 705–11; discussion 712. May 1998. doi:10.2165/00003495-199855050-00008. PMID 9585866. 
  9. ↑ "The role of topical retinoids in the treatment of photoaging". Drugs 65 (8): 1061–72. 2005. doi:10.2165/00003495-200565080-00003. PMID 15907143. 
  10. ↑ "A review of tazarotene in the treatment of photodamaged skin". Clin Interv Aging 3 (1): 71–6. 2008. doi:10.2147/cia.s1101. PMID 18488880. 
  11. ↑ 11.0 11.1 11.2 "Use of Topical Tazarotene for the Treatment of Acne Vulgaris in Pregnancy: A Literature Review". J Clin Aesthet Dermatol 13 (9): E59–E65. September 2020. PMID 33133344. 
  12. ↑ "Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety". Clin Interv Aging 1 (4): 327–48. 2006. doi:10.2147/ciia.2006.1.4.327. PMID 18046911. 
  13. ↑ 13.0 13.1 "Molecular mechanisms of tazarotene action in psoriasis". J Am Acad Dermatol 37 (2 Pt 3): S18–24. August 1997. doi:10.1016/S0190-9622(97)80396-9. PMID 9270552. 
  14. ↑ "Pharmacokinetics of tazarotene and acitretin in psoriasis". Expert Opin Drug Metab Toxicol 14 (9): 919–927. September 2018. doi:10.1080/17425255.2018.1515198. PMID 30134735. 
  15. ↑ 15.0 15.1 "Clinical pharmacokinetics and drug metabolism of tazarotene: a novel topical treatment for acne and psoriasis". Clin Pharmacokinet 37 (4): 273–87. October 1999. doi:10.2165/00003088-199937040-00001. PMID 10554045. 
  16. ↑ "Pharmacokinetics and safety review of tazarotene". J Am Acad Dermatol 39 (4 Pt 2): S134–8. October 1998. doi:10.1016/s0190-9622(98)70310-x. PMID 9777791. 
  17. ↑ "Pharmacokinetics and safety of tazarotene". J Am Acad Dermatol 43 (2 Pt 3): S31–5. August 2000. doi:10.1067/mjd.2000.108321. PMID 10898827. 
  18. ↑ Prepn: Chandraratna RA, EP patent 284288; idem, U.S. Patent 5,089,509 (1988, 1992 both to Allergan).



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