Tazarotene, commonly marketed as Tazorac, Avage, and Zorac is member of the acetylenic class of Retinoids: A Review

Mayur S. Jain*,  Dr. Shashikant D. Barhate1

1Shree Sureshdada Jain Institute of Pharmaceutical Education and Research, Jammer.

 

ABSTRACT:

Tazarotene is a third-generation prescription topical retinoid sold as a cream, gel, or foam. Tazarotene is a member of the acetylenic class of retinoids. This medication is approved for treatment of psoriasis, acne, and sun damaged skin (photodamage). It is commonly sold in two concentrations: 0.05% and 0.1%. Tazarotene, commonly marketed as Tazorac®, Avage®, and Zorac®, is member of the acetylenic class of retinoids. It is a prodrug that is found in topical formulations used in the treatment of various conditons, such as psoriasis, acne, and sun damaged skin (photodamage).

 

 

 

INTRODUCTION:

ethyl 6-[2-(4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyran-6-yl)ethynyl]pyridine-3-carboxylate

 

Chemical structure of Tazarotene

 

Tazarotene, commonly marketed as Tazorac®, Avage®, and Zorac®, is member of the acetylenic class of retinoids. It is a prodrug that is found in topical formulations used in the treatment of various conditons, such as psoriasis, acne, and sun damaged skin (photodamage). azarotene (marketed as Tazorac, Avage, Zorac, and Fabior) is a third-generation prescription topical retinoid sold as a cream, gel, or foam. Tazarotene is a member of the acetylenic class of retinoids.

 

This medication is approved for treatment of psoriasis, acne, and sun damaged skin (photodamage).^[1.2,] It is commonly sold in two concentrations: 0.05% and 0.1%.. Tazarotene is a retinoid prodrug which is converted to its active form, the cognate carboxylic acid of tazarotene, by rapid deesterification in animals and humans. Tazarotenic acid binds to all three members of the retinoic acid receptor (RAR) family: RARα, RARβ, and RARγ but shows relative selectivity for RARβ, and RARγ and may modify gene expression. The clinical significance of these findings is unknown.

 

Pharmacodynamics:

Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. When treating acne tazarotene may be taken in conjunction with an oral antibiotic. Tazarotene has been shown in peer-reviewed double blinded studies to reduce: mottling and hyperpigmentation, sallowness, fine wrinkling and coarse wrinkling in sun damaged skin. Histological studies have shown that long term (greater than 1 year) use of Tazarotene is associated with a significant reduction in atypical melanocytes and keratocytes - cells considered to be precursors of skin cancer. Some studies have shown long term use of Tazarotene to be associated with increased collagen production and better organization of skin collagen bundles.

 

Mechanism of action:

Although the exact mechanism of tazarotene action is not known, studies have shown that the active form of the drug (tazarotenic acid) binds to all three members of the retinoic acid receptor (RAR) family: RARa, RARb, and RARg, but shows relative selectivity for RARb, and RARg and may modify gene expression. It also has affinity for RXR receptors.^[2,3]

 

Tazarotene is a retinoid prodrug which is converted to its active form, the cognate carboxylic acid of tazarotene, by rapid deesterification in animals and humans. Tazarotenic acid binds to all three members of the retinoic acid receptor (RAR) family: RARα, RARβ, and RARγbut shows relative selectivity for RARβ, and RARγ and may modify gene expression. The clinical significance of these findings is unknown.

 

Absorption:

Minimal systemic absorption of tazarotene occurs due to its rapid metabolism in the skin to the active metabolite, tazarotenic acid, which can be systemically absorbed and further metabolized. Gender had no influence on the systemic bioavailability of tazarotenic acid.

 

Protein binding:

The active form of the drug, tazarotenic acid, is highly bound to plasma proteins (>99%).

 

Metabolism:

Undergoes esterase hydrolysis in skin to form its active metabolite, tazarotenic acid. Tazarotenic acid is further metabolized in skin and, after systemic absorption, hepatically metabolized to sulfoxides, sulfones, and other polar products for elimination.

 

Half life:

The half-life of the active form of the drug, tazarotenic acid, is approximately 18 hours in normal and psoriatic patients.

 

Toxicity:

Excessive topical use may lead to marked redness, peeling, or discomfort. Oral ingestion of the drug may affect liver function causing hypertriglyceridemia. Other symptoms may include conjunctival irritation, hair loss, headache, edema, fatigue, dermatitis, nausea, and visual disturbances. Oral administration of this material to rats and rabbits at doses of 0.20 mg/kg/day (rabbits) and 0.25 mg/kg/day (rats) resulted in developmental toxicity. A no effect level of 0.05 mg/kg/day was established. Similar teratogenic effects have been reported for other retinoid compounds. ^[2]

Side effects:

Common side effects include worsening of acne, increased sensitivity to sunlight, dry skin, itchiness, redness and in some cases extreme drying and cracking of skin. For most patients these side effects are uncomfortable but mild and decrease markedly after the first 2–4 weeks of use except for increased sensitivity to sunlight. ^[.3,4,]

 

For best results dermatologists recommend applying the cream or gel once daily before bedtime after washing the face with a mild cleanser. Dermatologists recommend using a moisturizer so that skin will not be as dry and flaky.

 

Uses:

Tazarotene is most commonly used topically to treat acne, psoriasis (a skin disease in which red, scaly patches form on some areas of the body), and to reduce skin wrinkling and liver spots. Tazarotene is rated pregnancy category X, and should not be used by pregnant women.

 

"There is limited evidence that tazarotene and isotretinoin benefit patients with moderate photodamage on the face: both are associated with skin irritation and erythema."

 

In addition to tretinoin, which has been associated with greater skin improvements with high concentrations, tazarotene and isotretinoin creams are also found to be effective for photodamage, but at the expense of skin irritation. More evidence is needed before any recommendations can be made on oral or topical polysaccharides or hydroxy acids. Evidence from one trial suggests that the effectiveness of 0.05% tretinoin, is equivalent to the effects of 0.05% and 0.1% tazarotene.^[2] However, for acne vulgaris, several recent double blind studies have shown consistently superior efficacy for tazarotene and roughly equal tolerability for both treatments.^[3]

 

"Specifically, tazarotene reduced the number of noninflammatory and inflammatory lesions at 4, 8, and 12 weeks -- all timepoints examined during treatment. Although the reduction of inflammatory lesions compared with tretinoin did not achieve statistical significance, the reduction of open comedones at 12 weeks was 65% for tazarotene vs 44% for tretinoin (P = .034). Tazarotene also proved superior in the reduction of noninflammatory lesions at 12 weeks (55% vs 42% for tretinoin, P = .042)

 

Synthesis:

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

 

 

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.^[4,5,]

 

CONCLUSIONS:

Tazarotene is most commonly used topically to treat acne, psoriasis (a skin disease in which red, scaly patches form on some areas of the body), and to reduce skin wrinkling and liver spots. Tazarotene is rated pregnancy category X, and should not be used by pregnant women.

 

"There is limited evidence that tazarotene and isotretinoin benefit patients with moderate photodamage on the face: both are associated with skin irritation and erythema."

 

REFERENCES:

1.     Baumann L, Vujevich J, Halem M, Martin LK, Kerdel F, Lazarus M, Pacheco H, Black L, Bryde J: Open-label pilot study of alitretinoin gel 0.1% in the treatment of photoaging. Cutis. 2005 Jul; 76(1):69-73. [PubMed:16144296]

2.     https://www.drugbank.ca/drugs/DB00799

3.     Chandraratna RA: Tazarotene--first of a new generation of receptor-selective retinoids. Br J Dermatol. 1996 Oct; 135 Suppl 49:18-25. [PubMed: 9035701].

4.     Tazarotene: MedlinePlus Drug Information". medlineplus.gov. Retrieved 2017-09-16.

5.     Prepn: R. A. S. Chandraratna, EP 284288; idem, U.S. Patent 5,089,509 (1988, 1992 both to Allergan).

6.     Meder W, Wendland M, Busmann A, Kutzleb C, Spodsberg N, John H, Richter R, Schleuder D, Meyer M, Forssmann WG: Characterization of human circulating TIG2 as a ligand for the orphan receptor ChemR23. FEBS Lett. 2003 Dec 18; 555(3):495-9. [PubMed:14675762].

 

 

 

Received on 16.05.2019        Accepted on 10.06.2019

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Asian J. Pharm. Res. 2019; 9(3):206-208.