Disposition and Biotransformation of the Acetylenic Retinoid Tazarotene in Humans

doi:10.1002/jps.20427

Journal of Pharmaceutical Sciences

Volume 94, Issue 10, October 2005, Pages 2246-2255

https://doi.org/10.1002/jps.20427 Get rights and content

ABSTRACT:

Oral tazarotene, an acetylenic retinoid, is in clinical development for the treatment of psoriasis. The disposition and biotransformation of tazarotene were investigated in six healthy male volunteers, following a single oral administration of a 6 mg (100 µCi) dose of [¹⁴C]tazarotene, in a gelatin capsule. Blood levels of radioactivity peaked 2 h postdose and then rapidly declined. Total recovery of radioactivity was 89.2 ± 8.0% of the administered dose, with 26.1 ± 4.2% in urine and 63.0 ± 7.0% in feces, within 7 days of dosing. Only tazarotenic acid, the principle active metabolite formed via esterase hydrolysis of tazarotene, was detected in blood. One major urinary oxidative metabolite, tazarotenic acid sulfoxide, accounted for 19.2 ± 3.0% of the dose. The majority of radioactivity recovered in the feces was attributed to tazarotenic acid representing 46.9 ± 9.9% of the dose and only 5.82 ± 3.84% of dose was excreted as unchanged tazarotene. Thus following oral administration, tazarotene was rapidly absorbed and underwent extensive hydrolysis to tazarotenic acid, the major circulating species in the blood that was then excreted unchanged in feces. A smaller fraction of tazarotenic acid was further metabolized to an inactive sulfoxide that was excreted in the urine. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association

Section snippets

INTRODUCTION

Tazarotene is a novel acetylenic retinoid known to be effective in the topical treatment of psoriasis, acne, and photodamaged skin.1., 2., 3. Tazarotene, a prodrug, was designed to undergo rapid and complete metabolism to its active metabolite tazarotenic acid. The exact mechanism of action of tazarotenic acid in the treatment of psoriasis and acne is unknown. However, it is thought that the selective interaction of tazarotenic acid with retinoic acid receptor (RAR), in particular RAR_β and RAR_γ

Study Design

This was a single-dose, single-center, open-label study characterizing the recovery of [¹⁴C]radioactivity and excretion pathways of [¹⁴C]tazarotene and its metabolites. A total of six healthy male subjects aged 18 to 45 years and willing to abstain from alcohol, xanthine-containing foods, or beverages and strenuous physical activity participated in this study. To ensure the protection of human subjects, this study was conducted in compliance with Informed Consent Regulations (U.S.21CFR Part 50),

Excretion and Recovery of Radioactivity

Following a single oral administration, to six healthy male volunteers, of 6 mg/100 µCi [¹⁴C]tazarotene, the [¹⁴C]derived radioactivity peaked rapidly 2 h postdose, with 96.7 ± 47.9 and 162 ± 30 ng-equivalents/g, in blood and plasma, respectively (Fig. 1). Subsequently, [¹⁴C]derived radioactivity concentrations declined rapidly and fell below the lower limit of quantitation in blood and plasma at 48 and 120 h postdose. The mean totals for radioactivity recovered in feces and urine were 63.0 ± 7.0% and

DISCUSSION

Retinoids such as vitamin A, isotretinoin, and tazarotene are effective in the treatment of a variety of dermatological disorders such as acne and psoriasis.⁹^,¹³^,¹⁴ However, special care must be taken when prescribing some of these drugs due to potential side effects. In particular, pregnancy prevention programs and washout periods are required for female patients in child-bearing years.¹³^,¹⁵ Retinoids play an important physiological role through activating gene transcription via specific

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Citation Excerpt :
Additionally, TZR was found to be highly susceptible in peroxide solutions, forming DP 1 (sulfoxide) and DP 3 (sulfone) as the major and minor products, respectively. Both DPs are also reported as a minor metabolites [5,7–9]. Among the two, DP 1 is previously known to originate in both oxidative and photolytic conditions [14].
Tazarotene is a prodrug that belongs to the acetylenic class of retinoids. The drug was subjected to hydrolytic, oxidative and photolytic stress testing to establish its comprehensive degradation chemistry. The drug proved to be unstable under acidic and basic hydrolytic conditions, yielding tazarotenic acid, which is a known major degradation product (DP) and an active metabolite. Additionally, two DPs each were generated upon interaction of drug and tazarotenic acid with HCl, used as an acid stressor. These were experimentally proven as pseudo DPs, as they did not originate when H₂SO₄ was employed as the stressor. The drug was also unstable under oxidative and photolytic conditions, yielding six DPs. All the products were separated on reversed phase (C18) column, using mobile phase composed of 10 mM ammonium formate (pH 3.5) and acetonitrile, which was run in a gradient mode. The separated DPs were subjected to LC-HRMS and LC-MSⁿ studies for their initial characterization. Seven hydrolytic and oxidative DPs that could be isolated using semi-preparative column were subjected to extensive 1D (¹H, ¹³C and DEPT-135) and 2D (COSY, HSQC and HMBC) NMR studies to confirm their structures. In total, five novel DPs were characterized, apart from two previously reported DPs, viz., tazarotenic acid and tazarotene sulfoxide, and four additional pseudo DPs. The complete degradation pathway of the drug was established. In silico ADMET properties of the drug and its DPs were evaluated using ADMET Predictor™.
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The most common undesirable side effects [6] during treatment are skin irritation, pruritus, erythema and a burning sensation, which occurred in 10–23% of patients using the cream formulation and 10–30% of patients using the gel one. Several analytical methods were used for the determination of Tz in the pharmaceutical formulations or in biological fluids [7–11]. The Sonogashira coupling reaction [12] between 4,4-dimethyl-6-ethynylthiochromane and 6-chloronicotinic acid ethyl ester is the most common synthetic method for the preparation of Tz.
New mononuclear copper(II) complexes of the first topical receptor-selective retinoid drug, Tazarotene (Tz), of the type [Cu(Tz)₂X₂] (X = Cl (1) and Br (2a)) were synthesized, characterized (elemental analysis, TG, FT IR, UV–Vis, EPR, magnetic susceptibility, molar conductance measurements and single crystal X-ray analysis) and tested for their antimicrobial activities against Staphylococcus aureus and Escherichia coli. Tazarotene behaves as a neutral monodentate ligand via the pyridine nitrogen atom. Complex 1 crystallizes in the monoclinic P2₁/c space group. The environment around the metal center in 1 could be described as an intermediate between tetrahedral and square–planar geometries. Crystals of the polymeric {[Cu(Tz)(μ-Br)]}_n (2b) complex were obtained by the slow evaporation of the reaction filtrate of complex 2a. The distorted tetrahedral environment around Cu(I) is formed from the pyridine N atom of Tz, the S atom of another Tz molecule as well as two bridged bromine atoms, with a Cu…Cu′ distance of 3.327 Å. Time-dependent density functional theory calculations were carried out to understand the electronic structure and to explain the related experimental findings. The electronic arrangement, type of hybridization and nature of bonding were obtained from natural bond orbital analysis.
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Disposition and Biotransformation of the Acetylenic Retinoid Tazarotene in Humans

ABSTRACT:

Section snippets

INTRODUCTION

Study Design

Excretion and Recovery of Radioactivity

DISCUSSION

J Am Acad Dermatol

J Biol Chem

J Pharm Sci

J Am Acad Dermatol

J Am Acad Dermatol

Tazarotene gel is safe and effective in the treatment of acne vulgaris: A multicenter, double-blind, vehicle-controlled study

Cutis

Efficacy of 0.1% tazarotene cream for the treatment of photodamage: A 12-month multicenter, randomized trial

Arch Dermatol

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

Br J Dermatol

Identification and characterization of a retinoid-induced class II tumor suppressor/growth regulatory gene

Proc Natl Acad Sci USA