Tazarotenic Acid Research Articles

Treatment of warty dyskeratoma with tazarotenic acid

A patient with warty dyskeratoma was successfully treated with tazarotenic acid gel. We present evidence to support that this did not occur by chance and suggest that tazarotenic acid be investigated further for the treatment of similar dyskeratatic disorders. (J Am Acad Dermatol 2002;46:S4.)

Pharmacokinetics and safety of tazarotene

The pharmacokinetic profile of tazarotene helps to ensure that systemic exposure to the drug and its metabolites is minimal. First, percutaneous penetration is limited, with less than 6% of the applied drug being absorbed into the bloodstream. Second, tazarotene is rapidly metabolized into tazarotenic acid and other metabolites that are not lipophilic. Third, tazarotene and its metabolites are rapidly eliminated from the blood in the urine and feces. These three pharmacokinetic features help to ensure that post-treatment plasma levels of tazarotene and its metabolites are comparable to those of endogenous retinoids, which suggests that the risk of teratogenic effects is minimal. Limited systemic exposure to the drug also ensures that any adverse effects are local effects rather than systemic effects. Overall, tazarotene has a good safety profile and is not associated with contact sensitization, phototoxicity, photoallergic reactions, mutagenicity, or carcinogenicity. (J Am Acad Dermatol 2000;43:S31-5.)

The role of tazarotene in the treatment of psoriasis.

The recent availability of tazarotene, the first receptor-selective retinoid, provides a much-needed addition to the therapeutic armamentarium for mild-to-moderate plaque psoriasis. Tazarotene gel offers a welcome combination of good efficacy and cosmetic acceptability, with minimal risk of systemic adverse effects. The selectivity of tazarotene for the beta and gamma subtypes of retinoic acid receptors suggests a targeted action on psoriatic keratinocytes, which may help to minimize the risk of adverse effects. The potential for adverse effects is further minimized by the limited transcutaneous absorption of tazarotene, its rapid metabolism into hydrophilic metabolites, and its rapid elimination from the body. These pharmacokinetic features ensure that plasma levels of tazarotene and its main metabolite, tazarotenic acid, are minimized--thus limiting systemic exposure. The hydrophilicity of the metabolites also limits systemic exposure by ensuring that accumulation does not occur in lipophilic tissues.

Clinical Pharmacokinetics and Drug Metabolism of Tazarotene

Tazarotene (AGN 190168) is a new acetylenic retinoid which is effective for the topical treatment of patients with stable plaque psoriasis and mild to moderate acne vulgaris. Topical gel application provides direct delivery of tazarotene into the skin. At 10 hours after a topical application of 0.1% tazarotene gel to the skin of healthy individuals and patients with psoriasis, approximately 4 to 6% of the dose resided in the stratum corneum and 2% of the dose distributed to the viable epidermis and dermis. Tazarotene is rapidly hydrolysed by esterases to its active metabolite, tazarotenic acid. Tazarotenic acid does not accumulate in adipose tissue, but undergoes further metabolism to its sulfoxide and to other polar metabolites and is rapidly eliminated via both urinary and faecal pathways with a terminal half-life of about 18 hours. Percutaneous absorption is similar between healthy individuals and patients with facial acne, leading to plasma concentrations below 1 microg/L. The systemic bioavailability of tazarotene (measured as tazarotenic acid) is low, approximately 1% after single and multiple topical applications to healthy skin. In patients with psoriasis under typical conditions of use, systemic bioavailability increased during the initial 2 weeks of treatment from 1% (single dose) to 5% or less (steady state). The increased bioavailability is probably related to decreases in plaque elevation and scaling due to successful treatment, resulting in a less effective skin penetration barrier to tazarotene. Steady-state concentrations of tazarotenic acid are achieved within 2 weeks of topical treatment in both healthy and psoriatic skin types. The large variability in plasma concentrations observed in patients with psoriasis is probably because of the large differences in lesional skin condition, the amount of drug applied and the surface area of application. There was no significant drug accumulation in the body with long term treatment of patients with psoriasis. Topical administration of tazarotene requires dosages much smaller than those usually required for oral retinoids, such as isotretinoin, acitretin and etretinate, and it delivers the drug directly into the target skin tissues. The low systemic absorption and rapid systemic elimination of tazarotene and tazarotenic acid results in limited systemic exposure. Thus, topical tazarotene has a low potential for systemic adverse effects and is effective in the treatment of patients with acne and psoriasis.

Pharmacokinetics and safety review of tazarotene

The safety profile of tazarotene is superior to that of orally administered retinoids. The limited percutaneous penetration of tazarotene limits its systemic absorption and this, combined with its rapid metabolism in the skin and the plasma to the more water-soluble active metabolite, tazarotenic acid, helps prevent accumulation of the drug in fat containing tissues. Urinary and fecal elimination are virtually complete within 2 to 3 days and 7 days after dosing, respectively. Tazarotene also exhibits no indication of mutagenicity, carcinogenicity, phototoxic potential, photoallergic potential, or contact sensitization. (J Am Acad Dermatol 1998;39:S134-8.)

Subchronic and Chronic Toxicity of Tazarotene Gel Following Topical Application in Hanford Miniswine

Tazarotene, a member of a novel class of synthetic acetylenic retinoids, is the first topical retinoid to demonstrate both efficacy and an acceptable patient tolerability profile in the treatment of psoriasis. The subchronic and chronic toxicity of topically applied tazarotene gel (0.025-0.1%; 0.05-0.5 mg/kg/d) was evaluated in Hanford miniswine in two separate, prospective, randomized, vehicle-controlled studies of 3 months' and 12 months' duration. Although tazarotenic acid, the active metabolite of tazarotene, was detected in the blood of animals in both studies, no signs of systemic toxicity could be detected in hematology, blood chemistry, posttreatment physical examination, necropsy, or histopathological examination of organ tissues. In both studies, the reversible signs and symptoms of cutaneous irritation caused by topical application of tazarotene gel were consistent with those effects commonly produced by other topical and oral retinoids.

Metabolic Deesterification of Tazarotene in Human Blood and Rat and HumanLiver Microsomes

Tazarotene is a novel acetylenic retinoid for the treatment of psoriasis and acne. We examined (1) the hydrolysis of tazarotene in blood from Japanese-American and Caucasian subjects, (2) the esterases responsible for this hydrolysis in human blood, and (3) tazarotene hydrolysis in rat and human liver microsomes. Tazarotene hydrolysis and enzyme inhibition were assessed by monitoring the disappearance of tazarotene and the appearance of its primary metabolite tazarotenic acid by HPLC. In blood, tazarotene was converted mainly to tazarotenic acid via first-order kinetics, and there was no statistically significant difference in the hydrolytic (metabolic) rate of tazarotene in uninhibited Japanese-American and Caucasian blood. Physostigmine (a cholinesterase inhibitor), bis(p-nitrophenyl) phosphate (a carboxylesterase inhibitor), and EDTA (an aromatic esterase inhibitor) did not significantly affect tazarotene hydrolysis in blood. Paraoxon, an inhibitor of all serine esterases including cholinesterase and carboxylesterase, decreased the hydrolysis of tazarotene to tazarotenic acid by 95% in both blood and liver microsomes. In conclusion, blood and liver esterases play a significant role in the hydrolysis of tazarotene to tazarotenic acid, and paraoxon-inhibitable forms of esterases are involved in this hydrolysis in humans.

Tazarotene: The first receptor-selective topical retinoid for the treatment of psoriasis

Tazarotene belongs to a novel, nonisomerizable class of retinoic acid receptor (RAR)-specific retinoids, the acetylenic retinoids, and is the first topical retinoid developed for the treatment of psoriasis. Tazarotene targets the keratinocyte and modulates the major causes of psoriasis. Tazarotene is rapidly metabolized by esterase to the active free acid tazarotenic acid, which is rapidly eliminated in animal species. Tazarotene selectively transactivates RARβ and RARγ subtypes and is inactive at retinoid X receptors (RXRs). This receptor selectivity could contribute to an optimized therapeutic index. Tazarotene has low systemic absorption after topical administration. In preclinical toxicity studies, high topical doses produced reversible topical irritation, and lower doses were well tolerated. Topical doses were neither teratogenic nor carcinogenic and were not sensitizing, phototoxic, or photosensitizing. The topical delivery of tazarotene and limited systemic exposure apparently result in a very low potential for systemic effects. (J Am Acad Dermatol 1997; 37: S12–S17.)

Tazarotene--first of a new generation of receptor-selective retinoids.

Tazarotene is a topically applied retinoid that targets the skin, the site of the fundamental defect(s) in psoriasis, modulating the major causes of the disease and achieving sustained efficacy. In vitro, binding of tazarotenic acid has been demonstrated to retinoic acid receptors (RARs), the probable molecular target of retinoid action in adult human skin, but not to retinoid X receptors (RXRs). In gene activation assays, tazarotene is selective for the RAR beta and RAR gamma subtypes. This selectivity could theoretically limit undesirable effects at the receptor level. In vitro, animal and clinical evidence reveals that topical tazarotene modulates all three pathogenic factors in psoriasis: abnormal keratinocyte differentiation, hyperproliferation, and increased expression of inflammatory markers. Tazarotene is minimally absorbed systemically after topical administration. Tazarotene is rapidly metabolized by esterase metabolism to its active free-acid form, tazarotenic acid, which has a relatively short elimination half-life (1-2 h). The pharmacokinetic profile of tazarotenic acid is predictable, with no significant accumulation. In preclinical toxicity studies, high topical doses produced only reversible topical irritation, and lower doses were well tolerated. Topical doses were neither carcinogenic nor teratogenic, had no effect on fertility or general reproduction, and were not phototoxic, sensitizing, or photoallergenic. The pharmacological selectivity of tazarotene and limited systemic exposure result in minimal systemic effects, while the lesser cytotoxic effects (relative to other retinoids) result in reduced local effects.