Tazarotene, sold under the brand name Tazorac, among others, is a third-generation prescription topical retinoid. It is primarily used for the treatment of

plaque psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete ...

and

acne Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...

. Tazarotene is also used as a therapeutic for photoaged and photodamaged skin. Tazarotene is a member of the acetylenic class of retinoids. It is available as a generic medication.

Medical uses

Tazarotene is most commonly used topically to treat acne vulgaris and

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete ...

. Like other topical retinoids, such as

tretinoin Tretinoin, also known as all-''trans'' retinoic acid (ATRA), is a medication used for the treatment of acne and acute promyelocytic leukemia. For acne, it is applied to the skin as a cream, gel or ointment. For leukemia, it is taken by mouth ...

and

adapalene Adapalene is a third-generation topical retinoid primarily used in the treatment of mild-moderate acne, and is also used off-label to treat keratosis pilaris as well as other skin conditions. Studies have found adapalene is as effective as othe ...

, tazarotene can be combined with benzoyl peroxide or an oral antibiotic, such as clindamycin or dapsone, for the treatment of acne. This results in increased efficacy compared to tazarotene

monotherapy Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a ''single'' disease, and often all the therapies are pharmaceutical (although it can also ...

. For psoriasis, a combination therapy of tazarotene and a mid- to high-potency corticosteroid is more effective than either treatment alone. Tazarotene can also be used for the treatment of photodamaged skin. It can reduce the clinical and

histological Histology, also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vis ...

signs of photodamaged skin. The therapy is more effective when used with the daily application of sunscreen.

Pregnancy

Before 2015, tazarotene was considered a Category X drug (meaning its use was contraindicated during pregnancy) according to

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) guidelines, despite demonstrating similar plasma retinoid levels as adapalene and tretinoin, which were classified as Category C drugs. 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. 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.

Contraindications

Tazarotene is contraindicated for use in patients who are known to be or suspected of being pregnant. Tazarotene is a known teratogen. It is also contraindicated in patients with a known

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune ...

to any ingredient in the specific

pharmaceutical formulation Pharmaceutical formulation, in pharmaceutics, is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product. The word ''formulation'' is often used in a way that includes dosage ...

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 Mometasone, also known as mometasone y 3 s, is a steroid medication used to treat certain skin conditions, hay fever, and asthma. Specifically it is used to prevent rather than treat asthma attacks. It can be applied to the skin, inhaled, or use ...

fluocinonide Fluocinonide (sold under various brand names) is a potent glucocorticoid used topically as an anti-inflammatory agent for the treatment of skin disorders such as eczema and seborrhoeic dermatitis. It relieves itching, redness, dryness, crusti ...

. These effects tend to be mild to moderate, and increase in intensity as tazarotene concentration increases.

Pharmacology

Mechanism of action

Tazarotene is selective for two types of retinoic acid receptors,

RAR-γ Retinoic acid receptor gamma (RAR-γ), also known as NR1B3 (nuclear receptor subfamily 1, group B, member 3) is a nuclear receptor encoded by the ''RARG'' gene. Adapalene selectively targets retinoic acid receptor beta and retinoic acid receptor ...

and RAR-β. Like all retinoids, it affects the ability of

keratinocytes Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referre ...

in the epidermis to proliferate and differentiate. It does so by upregulating

filaggrin Filaggrin (filament aggregating protein) is a filament-associated protein that binds to keratin fibers in epithelial cells. Ten to twelve filaggrin units are post-translationally hydrolyzed from a large profilaggrin precursor protein during termi ...

expression and downregulating the expression of keratinocyte transglutaminase,

ornithine decarboxylase The enzyme ornithine decarboxylase (, ODC) catalyzes the decarboxylation of ornithine (a product of the urea cycle) to form putrescine. This reaction is the committed step in polyamine synthesis. In humans, this protein has 461 amino acids a ...

involucrin Involucrin is a protein component of human skin and in humans is encoded by the ''IVL'' gene. In binding the protein loricrin, involucrin contributes to the formation of a cell envelope that protects corneocytes in the skin. Gene This gene i ...

epidermal growth factor receptor The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The epidermal growth factor rece ...

, and various

keratins Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. Alpha-keratin (α-keratin) is a type of keratin found in vertebrates. It is the key structural material making up scales, hair, nails, feathers, ho ...

Pharmacokinetics

More than 99% of tazarotenic acid, the active metabolite of tazarotene, in the blood binds to plasma proteins (the most predominant being

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...

). The

volume of distribution In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...

(V_D) for tazarotene is 26.1 L/kg and the V_D for tazarotenic acid is 1.97 L/kg. Tazarotene is excreted from the body via feces and urine equally, and it has an elimination half-life of 16 to 18 hours.

Synthesis

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

The formation of the ring system involves first alkylation of the anion from

thiophenol Thiophenol is an organosulfur compound with the formula C6H5SH, sometimes abbreviated as PhSH. This foul-smelling colorless liquid is the simplest aromatic thiol. The chemical structures of thiophenol and its derivatives are analogous to phen ...

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 Acetyl chloride (CH3COCl) is an acyl chloride derived from acetic acid. It belongs to the class of organic compounds called acid halides. It is a colorless, corrosive, volatile liquid. Its formula is commonly abbreviated to AcCl. Synthesis On a ...

in the presence of

aluminium chloride Aluminium chloride, also known as aluminium trichloride, is an inorganic compound with the formula . It forms hexahydrate with the formula , containing six water molecules of hydration. Both are colourless crystals, but samples are often contam ...

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

{{Retinoid receptor modulators Retinoids Benzene derivatives Alkyne derivatives Nicotinate esters Anti-acne preparations Antipsoriatics Ethyl esters