Retinoic acid

Absorption

Tretinoin applied topically is expected to remain on the stratum corneum and undergo minimal systemic absorption. In one study, the topical application of radiolabelled tretinoin for 28 days was associated with a total percutaneous absorption of 2%.
The extent of absorption was examined after a once-daily application of 1.9 g of the combination product with benzoyl peroxide for 14 days. On Day 14, at steady-state, the mean Cmax was 0.15-0.19 ng/mL for tretinoin, 0.27-0.34 ng/mL for the metabolite 4-keto 13-cis retinoic acid, and 0.13-0.28 ng/mL for 13-cis retinoic acid, respectively. The Cmax varied across different age groups (children, adolescents, and adults). The corresponding ranges for the mean AUC0-24 were 0.63-2.06, 2.39-2.89, and 0.96-1.99 ng*h/mL.
Following oral administration, the absolute bioavailability of tretinoin was approximately 50%. While the effect of food on tretinoin is unclear, food increases the oral absorption of retinoids, as a class. When the oral dose of 22.5 mg/m2 tretinoin was administered twice daily, the mean ± SD Cmax was 394 ± 89 ng/mL after the first dose and 138 ± 139 ng/mL after one week of continuous treatment. The area under the curve (AUC) was 537 ± 191 ng·h/mL after the first dose and 249 ± 185 ng·h/mL after one week of continuous treatment. The Tmax was between one and two hours.

Toxicity

The oral LD50 in rats is 2000 mg/kg. The dermal LD50 in rabbits is >2500 mg/kg.
Reversible signs of hypervitaminosis A, such as headache, nausea, vomiting, and mucocutaneous symptoms, are expected to appear in tretinoin overdose. Overdosage with other retinoids has been associated with transient headache, facial flushing, cheilosis, abdominal pain, dizziness and ataxia: these symptoms have quickly resolved without apparent residual effects. here is no specific treatment in the case of an overdose and it is advised to treat patients experiencing tretinoin overdose in a special hematological unit.

Description

all-trans Retinoic acid is a metabolite of vitamin A and a ligand for retinoic acid receptors (RARs) with IC₅₀ values of 9, 3, and 10 nM for RARα, RARβ, and RARγ, respectively, in radioligand binding assays. It induces expression of a luciferase reporter in COS-7 cells expressing RARα, RARβ, or RARγ (EC₅₀s = 169, 9, and 2 nM, respectively). all-trans Retinoic acid (17 nmol) reduces papilloma formation induced by phorbol 12-myristate 13-acetate (TPA; ) in mice. It reduces bile duct proliferation, hydroxyproline levels, and liver inflammation in a rat model of α-naphthylisothiocyanate-induced chronic cholestasis and reduces plasma levels of alkaline phosphatase and bile salts in the Mdr2^-/- mouse model of cholestasis. all-trans Retinoic acid also reduces hepatic fat accumulation, triglycerides, body weight, and serum glucose levels in mice with Western diet-induced obesity.

Description

Vitamin A, or retinol, is produced from carotenoids in the livers of animals. It is also broadly defined as a series of compounds that have structures similar to retinol. It is essential for growth and development, and for strong vision. Retinoic acid is a metabolite of vitamin A that mediates the vitamin’s functions.
Recently, H. Veiga-Fernandes and co-workers at the Institute of Molecular Medicine (Lisbon) discovered that vitamin A is not only necessary for animals’ health, but?it also may be essential for setting up the immune system before birth, when fetuses are in utero. They found that pregnant mice with vitamin A–poor diets produce babies with small lymph nodes and consequently weak immune systems. Retinoic acid produced from the mother’s vitamin A activates a gene that produces a hormone receptor that mediates the growth of lymphoid cells.

The Uses of Retinoic acid

Physiological metabolite of vitamin A. Effects gene expression via nuclear retinoic acid receptors (RAR); mediates cellular growth and differentiation

What are the applications of Application

Retinoic Acid, all trans is an oxidized carboxylic acid form of Vitamin A, and an activator of RAR and RXR and used in stem cells

Background

Tretinoin, also known as all-trans-retinoic acid (ATRA), is a naturally occurring derivative of vitamin A (retinol). It is an oxidation product in the physiological pathway of vitamin A metabolism. In human circulation, tretinoin is normally found at very low concentrations, approximately 4 to 14 nmol/L. Tretinoin exhibits anti-inflammatory, antineoplastic, antioxidant, and free radical-scavenging activities. It has been used in dermatology for many years to treat various skin conditions ranging from acne to wrinkles and activates nuclear receptors to regulate epithelial cell growth and differentiation. Tretinoin is given orally to treat acute promyelocytic leukemia and topically to treat skin conditions such as acne.

Indications

Oral tretinoin is indicated for induction of remission in adults and pediatric patients one year of age and older with acute promyelocytic leukemia (APL), characterized by the presence of t(15;17) translocation or presence of PML/RARα gene expression and who are refractory to or who have relapsed from anthracycline chemotherapy or for whom anthracycline-based chemotherapy is contraindicated.
Topical tretinoin is also indicated alone or in combination with benzoyl peroxide or clindamycin for the treatment of acne vulgaris. It is also used in prescription and over-the-counter for treating various skin conditions such as melasma, hyperpigmentation, and photoaging alone or in combination with other drugs.

Pharmacokinetics

Tretinoin is a vitamin A derivative that promotes cell production, proliferation, and differentiation. When used topically, tretinoin regulates epidermal cell turnover and collagen production. It also prevents collagen loss, reduces inflammation, and blocks the induction of matrix metalloproteinase (MMP), which are enzymes that disrupt collagen and elastic fibres. In short-term and long-term studies, topical application of tretinoin at doses ranging from 0.001% to 0.1% was associated with improvements in clinical signs of photoaging and fine wrinkles, increased epidermal thickness, compaction of the stratum corneum, and decreased melanin content. It also improved melanocyte differentiation and distribution, promotion of epidermal hyperplasia, and angiogenesis.
Tretinoin exhibits antineoplastic activities when given orally. Tretinoin was shown to induce differentiation in tumour cells. It induced cytodifferentiation and decreased acute promyelocytic leukemia (APL) cell proliferation in culture and in vivo. In patients with APL, tretinoin promoted the initial maturation of the primitive promyelocytes derived from the leukemic clone, followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete remission.

Metabolism

Tretinoin is rapidly metabolized to form various oxidized and conjugated metabolites. It forms several metabolites stereoisomerization derivatives (9-cis-retinoic acid or alitretinoin and 13-cis-retinoic acid or isotretinoin), oxidation derivatives (4-hydroxy-retinoic acid, 4-oxo-retinoic acid, 18-hydroxy-retinoic acid, 5,6-epoxy-retinoic acid, 3,4-didehydro-retinoic acid and retinotaurine), stereoisomerization and oxidation derivatives (13-cis-4-oxo-retinoic acid), glucuronidation derivatives (retinoyl beta-glucuronide, 13-cis-retinoyl beta-glucuronide, 4-oxo-retinoyl beta-glucuronide, 5,6-epoxyretinoyl beta-glucuronide and 13-cis-4-oxo-retinoyl beta-glucuronide), nonpolar metabolites of retinoic acid, and retinoic acid esters.
Tretinoin is metabolized by several CYP enzymes, including CYP3A4, CYP2C8, and CYP2E. It also undergoes glucuronidation by UGT2B7. The metabolites 4-oxo retinoic acid and 4-oxo trans retinoic acid glucuronide have one-third of the pharmacological activity of the parent compound. When the plasma concentrations decreased to one-third of their day-one concentrations after one week of continuous therapy, tretinoin induced its own metabolism.