Acitretin, Isotretinoin and Bexarotene
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REVIEW ARTICLE A review of three systemic retinoids in dermatology: acitretin, isotretinoin and bexarotene Hossein Mortazavi, MD 1,2 Retinoids are synthetic and natural analogues of vitamin A that Nessa Aghazadeh, MD 1 have various effects on cellular differentiation, cellular proliferation, Maryam Ghiasi, MD 1 immune system, and embryonic development. The present study reviews the history of systemic retinoids in medicine, the structure Vahideh Lajevardi, MD 1 of synthetic retinoids and their mechanisms. The main focus is on their biologic functions, clinical uses, and the adverse effects 1. Department of Dermatology, Tehran of isotretinoin, acitretin, and bexarotene representing the most University of Medical Sciences, commonly used first, second, and third generation systemic Tehran, Iran 2. Autoimmune Bullous Diseases retinoids, respectively. Research Center, Tehran University Keywords: acitretin, bexarotene, etretinate, isotretinoin, retinoids of Medical Sciences, Tehran, Iran Iran J Dermatol 2013; 16: 144-158 Corresponding Author: Hossein Mortazavi, MD Razi Hospital, Vahdat Islamic Square, Tehran, Iran Email: [email protected] Conflict of interest: none to declare Received: 18 October 2013 Accepted: 24 November 2013 effects of retinoids has led to various clinical INTRODUCTION applications of these drugs in dermatology and The term “retinoid” applies to the synthetic and oncology 1. natural analogues of vitamin A 1. Retinoids show The introduction of isotretinoin, etretinate, and biologic activities that are specific to vitamin A. its active metabolite acitretin and bexarotene, To enhance the beneficial effects of vitamin A, the RXR-selective retinoid, to dermatology has especially its anti-keratinization property and revolutionized medical therapy in dermatology 1,4. the promotion of cellular differentiation, new synthetic retinoids were engineered 2, 3. Generally, HISTORY retinoids bind to specific nuclear receptors and consequently activate these receptors. However, In 1909, Step found that egg-yolk extract these bindings are not an essential prerequisite contained a vital substance. Soon afterwards, for their functions. Binding to complex groups of this substance, first named fat soluble A and then intra nuclear receptors (retinoic acid receptors: vitamin A, was also found in other natural resources RARs and retinoid X receptors: RXRs) is the such as milk cream and cod liver oil. The proper cornerstone of understanding the basic mechanisms beta carotene formula was discovered by Karrer of retinoids 4. Retinoids are involved in diverse et al in 1931 5. In 1937, vitamin A was synthesized biological activities including cellular growth, for the first time. In 1976, Michael Sporn and his cellular cohesion, immunomodulatory effects, and colleagues used the term ‘Retinoid’ for the first anti-tumor functions 3. The diversity of biologic time 4. 144 Iranian Journal of Dermatology © 2013 Iranian Society of Dermatology A review of systemic retinoids BASIC KNOWLEDGE ON RETINOIDS is produced through the cyclization of the polyene side-chain 2,7. This group includes bexarotene, Chemical structure tazarotene, and adapalene. The biochemical structure of vitamin A (retinol) is composed of three major units: the cyclic end Therapeutic index of retinoids group (cyclic ring), the polyene side chain, and the polar end (Figure 1). Modifications in any of The therapeutic index (TI) of retinoids is defined these three components results in the production of as the ratio of the lowest intraperitoneal dose per different synthetic retinoids 6. The first generation day causing hypervitaminosis A after 14 days, to of retinoids (non-aromatics) including tretinoin (all- the lowest intraperitoneal dose per week causing trans-retinoic acid), isotretinoin and alitretinoin, a regression of papillomas by 50% after 14 days 5,7. are synthesized by chemical modification of the For instance, the TI of tretinoin and isotretinoin polar end and polyene side chain. Replacing the is as follows: cyclic end group of vitamin A with substituted Tretinoin (All-trans Retinoic Acid: ATRA) TI = 0.2 and non-substituted rings results in the formation Isotretinoin TI = 0.5 of the second generation of retinoids (mono- aromatics) including etretinate and acitretin. The From vitamin A to retinoic acid (vitamin A third generation of retinoids, also called arotinoids, metabolism) Vitamin A is not synthesized in the human body. Therefore, it should be supplied from dietary regiments 4. Vitamin A is found in three inter- convertible forms; retinol (vitamin A alcohol) which is the main dietary, transport and storage form 3, retinal (vitamin A aldehyde) which is necessary for visual function 5, and retinoic acid (vitamin A acid) 3, which is the biologically active ligand that can bind to intracellular retinoid receptors 3. Retinyl esters are hydrolyzed to retinol in the intestinal lumen. Next, it is absorbed and stored in the liver. Subsequently, retinol is converted to retinoic acid 3. Retinoic acid is predominantly found in all-trans form (ATRA) and only a small fraction of it is isomerized into 13-cis retinoic 2. Transport of retinoids Retinoic acids are transported in blood stream by albumin. Two intracellular carriers named cytosolic retinoic acid binding protein1 and 2 (CRABP1, 2) transport retinoic acids into the nucleus. These carriers have important regulatory functions, as well. CRABP-1 regulates the levels of retinoic acid in different tissues and CRABP-2 is the main form in the human epidermis and mediates the morphogenic activity of vitamin A. In fact, CRABP-2 is an important mediator in epidermal differentiation; extremely high levels of CRABP-2 are found in the psoriatic skin (800% Figure 1. Chemical Structure of Retinoids increase compared to normal skin) as well as in Iranian Journal of Dermatology, Vol 16, No 4, Winter 2013 145 Mortazavi et al other disorders of keratinization such as ichthyosis, metabolized in the liver 2. Isotretinoin is oxidized Darier disease, pityriasis rubra pilaris and keratosis to 4-oxo-isotretinoin which is quickly eliminated pilaris. It has been shown that treatment with by the liver and the kidney 3. In contrast to retinoids reduces the expression of epidermal vitamin A, isotretinoin is not stored in the liver or CRABP-2. Interestingly, higher levels of CRABP adipose tissue 3. Acitretin is metabolized through may be associated with increased sensitivity of isomerization, forming cis-acitretin 2. Bexarotene the lesion to retinoids 2. is metabolized by cytochrome P450 3A4 3. It is oxidized to 6- and 7-hydroxy-bexarotene and subsequently to 6- and 7-oxo-bexarotene 2. Retinoid receptors and mechanism of action These receptors belong to the superfamily of Half-Lives ligand-activated nuclear receptors, including receptors of vitamin D, thyroid hormone, steroid Teratogenicity is a major concern in the and peroxisome proliferator activated receptor administration of systemic retinoids. Therefore, (PPAR) 8. Two distinct families of retinoid receptors the length of the time these drugs are present in are found: retinoic acid receptor (RARs) and the body is crucial; terminal elimination half-lives retinoic X receptors (RXRs). Each family has three of retinoids are 10 to 20 hours for isotretinoin, 50 isoforms encoded by different genes: alpha (α), hours for acitretin, 7 to 9 hours for bexarotene and beta (β) and gamma (γ). Retinoids have different as long as 80 to 160 days for etretinate 2. receptor binding properties. ATRA binds only to Unlike isotretinoin and acitretin, etretinate is RAR, while 9-cis-retinoic acid is the only known highly lipophilic, approximately 50 times more physiologic ligand for RXR. Bexarotene is an lipophilic than acitretin. Therefore, it can be stored in example of highly selective RXR-binding synthetic adipose tissues for several years. In fact, the serum retinoids (rexinoids) 2,4,9. Briefly, through three level of etretinate is markedly decreased after the mechanisms, retinoid receptors modulate gene discontinuation of treatment. However, low levels expression: first, transactivation via direct binding of circulating etretinate may be detectable for up to retinoic acid–response elements (RARE)in to 2.9 years after discontinuation of the drug 2. The target gene promoters; second, transrepression of pharmacologic properties of isotretinoin, acitretin, activator protein 1 (AP-1) and other transcription etretinate and bexarotene are summarized in Table 1. factors; third, protein–protein interactions and competition with other nuclear receptors (Vitamin Acitretin re-esterification (reverse metabolism) D Receptor, VDR) 4. Oral alcohol intake promotes the re-esterification of acitretin to etretinate. In the human hepatocytes Pharmacokinetics of systemic retinoids culture, this conversion only occurs in simultaneous presence of ethanol and acitretin. In a study on 10 Metabolism psoriatic patients, the plasma level of etretinate Generally, the bioavailability of oral retinoids is reached 2.5-56.7 nanograms per milliliter (ng/ml) increased when administered with food, especially three months after their treatment with a daily with fatty meals 2. Systemic retinoids are transported acitretin dose of 30 mg. in the blood stream by albumin, lipoproteins, or In another study, the concentration of etretinate other plasma proteins and are mainly stored and in subcutaneous fat tissues was 100 times greater Table 1. Pharmacologic properties of systemic retinoids Peak Level Retinoid Bioavailability Protein Binding Half-life Metabolism