Tretinoin, ATRA
Altinac™, Avita™, Renova®, Retin-A®, Vesanoid® | Retin-A® Micro | Tretinoin
Classification:
Antineoplastic Agents
Dermatological Agents
Dermatological Agents
Dermatological Agents
Description: Tretinoin, also known as all-trans-retinoic acid (ATRA), is a naturally occurring derivative of vitamin A. As vitamin A (retinol) derivatives, retinoids are important regulators of cell reproduction, and cell proliferation and differentiation; however, unlike vitamin A, retinoids are not converted into rhodopsin, which is needed for night vision. Topical tretinoin is indicated in the treatment of mild to moderate acne (e.g., grades I-III) and photodamaged skin. Topical tretinoin has also been used in the symptomatic management of keratinization disorders such as ichthyosis and keratosis follicularis. Tretinoin represents a new class of anticancer drugs, differentiating agents. Oral tretinoin is used in the treatment of acute promyelocytic leukemia (APL) and is undergoing phase III investigation in the treatment of Kaposi’s sarcoma. In the treatment of APL, tretinoin offers a less toxic means to induce complete remission than conventional chemotherapy. The FDA originally approved tretinoin as a topical agent in 1971, and tretinoin capsules (Vesanoid®) were approved in November 1995. A NDA for a liposomal intravenous form of ATRA (Atragen®) in the treatment of APL was denied by the FDA in January 2001.
Mechanism of Action: Retinoids are intracrine and paracrine mediators of cell differentiation and proliferation, apoptosis (programmed cell death), and reproduction. Cells regulate the formation of specific retinoid isomers depending upon the cellular action required. The numerous effects of retinoids reflect the complex biology of the nuclear receptors that mediate retinoid activity. Retinoid receptors are divided into retinoid X receptors (RXRs) and retinoic acid receptors (RARs); both types can be further divided into 3 subtypes: Alpha, beta, and gamma. These receptor subtypes are further divided into many isoforms. Retinoid receptors are structurally similar but have different affinities for different types of retinoids and distribution varies throughout the body resulting in a wide range of actions. Tretinoin binds to all three RARs, but does not bind to RXRs except at very high concentrations. RAR-alpha and RAR-beta have been associated with the development of acute promyelocytic leukemia and squamous cell cancers, respectively. RAR-gamma is associated with retinoid effects on mucocutaneous tissues and bone.
Skin Disorders: By binding to RARs, tretinoin modifies gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation. It has not been established whether the clinical effects of tretinoin are mediated through activation of RARs, other mechanisms such as irritation, or both. Tretinoin appears to prevent horny cell cohesion and to increase epidermal cell turnover and mitotic activity. Subsequently, in patients with acne, expulsion of existing comedones occurs, and formation of new comedones is prevented through sloughing and expulsion of horny cells from the follicle. Tretinoin reduces the cell layers of the stratum corneum. The bacterium involved in acne, Propionibacterium acnes, and sebum production are unaffected. An additional action of tretinoin may involve keratinization inhibition, which would explain its effectiveness in treating keratinization disorders.
Photodamage: Topical tretinoin is effective in reducing fine wrinkling, mottled hyperpigmentation, roughness, and laxity associated with photodamaged skin. Ultraviolet irradiation induces three metalloproteinases in human skin: collagenase, 92-kd gelatinase, and stromelysin-1. The combined actions of these enzymes can fully degrade skin collagen. Pretreatment of skin with tretinoin inhibits the induction of these skin matrix metalloproteinase proteins and activity by 70 - 80% in both connective tissue and outer layers of irradiated skin.
Acute Promyelocytic Leukemia: Similar to other retinoids, tretinoin induces cellular differentiation in malignant cells. Acute promyelocytic leukemia (APL) is caused by a genetic lesion that disrupts the alpha retinoic acid receptor (RAR-alpha) gene found on the long arm of chromosome 17 and the PML gene found on chromosome 15. The fusion protein that is formed, PML-RAR-alpha, inhibits apoptotic pathways and blocks myeloid differentiation when present in levels greater than those of the normal RAR-alpha protein. The presence of this gene translocation [t(15;17)] is used for diagnosis of APL and as a marker of response following treatment with either cytotoxic agents or tretinoin. During tretinoin treatment, cells expressing PML/RAR-alpha undergo cellular differentiation at a rate higher than normal cells. At therapeutic doses of tretinoin, the activity of the fusion protein on differentiation converts from inhibitory to stimulatory. Terminal differentiation of APL cells as the mechanism of tretinoin therapy is supported by 1) the absence of bone marrow aplasia during treatment; 2) the appearance of cells during treatment with the morphologic characteristics of maturation stages intermediate between promyelocytes and neutrophils; 3) the presence, during treatment, of PML and RAR-alpha rearrangements in peripheral blood neutrophils that disappear after treatment. Treatment with tretinoin reverses the bleeding diathesis seen in APL, before any morphologic response is noted. A retinoic acid syndrome, similar to capillary leak syndrome, may be seen in some patients (see Adverse Reactions). The etiology of this syndrome is unknown, but may be due to decreases in leukocyte adhesion protein activity. Resistance to tretinoin may develop due to pharmacokinetic reasons (decreased bioavailability) and/or changes in proteins involved in the cellular activity of tretinoin.
Pharmacokinetics: Tretinoin is administered topically and orally; an intravenous formulation is under investigation. Following topical application, a minimal amount of drug is absorbed systemically. Prolonged treatment or application to large body surface areas can enhance systemic absorption. After administration of a single oral dose, tretinoin is well absorbed, with peak plasma concentrations showing considerable interpatient variability. Mean peak plasma concentrations are 347 plus or minus 266 ng/ml and occur between 1 and 3 hours after dosing. Systemic tretinoin is greater than 95% bound to plasma proteins, primarily albumin. The distribution of tretinoin has not been determined. Tretinoin is metabolized by the cytochrome P450 hepatic enzyme system. The metabolites include 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo trans retinoic acid glucuronide. Tretinoin appears to induce its own metabolism. An approximately 10-fold increase in the urinary excretion of 4-oxo trans retinoic acid glucuronide is observed after 2 - 6 weeks of continuous dosing when compared with baseline. One of the proposed benefits of the liposomal injection form of tretinoin, is the ability to overcome excessively rapid hepatic clearance and subsequent drug resistance associated with oral administration. The elimination half-life is about 0.5 - 2 hours in patients with APL. Approximately 1 - 5% of a topically applied dose is excreted in the urine within 24 hours, and about 90% of an oral dose is excreted in the urine and feces within 72 hours and 6 days, respectively.
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References
. Muindi J, Frankel SR, Miller WH Jr, et al. Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid “resistance” in patients with acute promyelocytic leukemia. Blood 1992;79:299 - 303.
. Frankel SR. Eardley A, Heller G et al. All-trans retinoic acid for acute promyelocytic leukemia. Ann Intern Med 1994;120:278 - 86.
. Grignani F, Fagioli M, Alcalay M, et al. Acute promyelocytic leukemia: from genetics to treatment. Blood 1994;83:10 - 25.
. Fisher GJ, Wang Z, Datta SC et al. Pathophysiology of premature skin aging induced by ultraviolet light. N Engl J Med 1997;337:1419 - 28.
[ Revised 10/28/2005 2:56:00 PM ]
Related entries
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