Retinoid metabolites

Pharmacology Tretinoin is a retinoid metabolite of vitamin A. Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical tretinoin P.1223... 

Finally, an abundant protein in the RPE, RPE65, seems to play a role in the retinoid cycle, but the exact role remains a mystery. Mice lacking this protein accumulate all-trans-retinyl esters that concentrate within lipid droplets in RPE cells (84). These mice are completely devoid of 11-cis-retinal and other cis-retinoid metabolites and are severely com-... 

The following retinoid metabolites have been prepared in a labeled form. 

For several other retinoids, actual spectral data have not been published, but characteristic fragmentation patterns have been reported. These compounds include three urinary metabolites of retinoic acid in which the chain is shortened and the cyclohexenyl ring is oxidized (Hanni et al., 1976 see Fig. 7b, Chapter 11), three fecal metabolites of retinoic acid (4-oxoretinoic acid and two hydrox-ylated metabolites, see Fig. 6, Chapter 11 Hanni and Bigler, 1977), several metabolites (Hanni et al., 1972 see Fig. 14, Chapter 11) and isomers (Englert et al., 1978) of etretinate, 3-hydroxyanhydroretinol, a metabolite of 3-hy-droxyretinol (Barua et al., 1979), and a 4-oxo-Ci9 aldehyde metabolite of retinoic acid (Rockley et al., 1980 see Fig, 8, Chapter 11). With the advent of HPLC and an increase in the sensitivity of mass spectrometry, this technique should continue to be of great usefulness for the identification of retinoid metabolites. 

Several hundred retinoids have been tested in this assay, and some of the more important results are summarized in Table II. With the exception of the new retinoidal benzoic acid derivatives, few analogs have been made that are more active than either al -trans- or 13-c/.y-retinoic acid. There is little or no evidence at present that any natural known retinoid metabolite is more active in tracheal... 

It should be mentioned that most structural studies on retinoid metabolites have been performed after administration. of retinoic acid to the animal. Because it is likely that at least some retinol is metabolized through retinoic acid, many of the metabolites identified for retinoic acid are probably also metabolites of retinol. These compounds, derived fixrm retinoic acid, are discussed in Section II,D,2. 

Fig. 5. Metabolites of retinoic acid in rat feces after a pharmacological dose of retinoic acid. Vitamin A-normal rats were administered an intraperitoneal dose of 27.2 mg all-rran.r-Fetinoic acid. Feces were collected over a 5-day period and extracted. The retinoid metabolites were purified to homogeneity and identified by mass spectrometry and proton magnetic resonance spectroscopy (Hanni and Bigler, 1977).

Upregulation of retinoid receptor expression and function by provitamin A carotenoids may play a role in mediating the growth inhibitory effects of retinoids in cancer cells (Lian et al. 2006, Prakash et al. 2004). However, it is unclear if non-provitamin A carotenoids and their metabolites may act... 

Tazarotene (Tazorac) is a synthetic retinoid that is hydrolyzed to its active metabolite, tazarotenic acid, which modulates keratinocyte proliferation and differentiation. It is available as a 0.05% or 0.1% gel and cream and is applied once daily (usually in the evening) for mild to moderate plaque psoriasis. Adverse effects are dose- and frequency related and include mild to moderate pruritus, burning, stinging, and erythema. Application of the gel to eczematous skin or to more than 20% of body surface area is not recommended because this may lead to extensive systemic absorption. Tazarotene is often used with topical corticosteroids to decrease local adverse effects and increase efficacy. 

The central cleavage of P-carotene 1 is most likely the major pathway by which mammals produce the required retinoids il), in particular, retinal 2, which is essential for vision and is subsequently oxidized to retinoic acid 3 and reduced to retinol 4. An alternative excentric cleavage of 1 has been reported involving scission of the double bond at C7-C8 producing P-8 -apocarotenal 5 (2a,2b) which is subsequently oxidized to 2 (Fig. 1) (2c). The significance of carotene metabolites such as 2, 3 and 4 to embryonic development and other vital processes such as skin and membrane protection is a major concern of medicinal chemistry. 

All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotretinoin to adult cystic acne patients (18 years of age and older), the exposure of patients to 4-oxo-isotretinoin at steady state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin. In vitro studies indicated that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces. 

This class includes both vitamin A and the provitamin A carotenoids. All the compounds related to all-trani-retinol (Figure 19.11) are known as vitamin A. These compounds, together with their metabolites and synthetic derivatives, exhibiting the same properties are called retinoids. Vitamin A is found in animal products as retinyl esters (mainly palmitate). 

It is a metabolite of the aromatic retinoid, etretinate used in the treatment of psoriasis. 

It is an acetylenic retinoid prodrug which is hydrolysed to active metabolite tazarotenic acid, binds to retinoic acid receptors resulting in modified gene expression. 

Acitretin (Soriatane), a metabolite of the aromatic retinoid etretinate, is quite effective in the treatment of psoriasis, especially pustular forms. It is given orally at a dosage of 25-50 mg/d. Adverse effects attributable to acitretin therapy are similar to those seen with isotretinoin and resemble hypervitaminosis A. Elevations in cholesterol and triglycerides may be noted with acitretin, and hepatotoxicity with liver enzyme elevations has been reported. Acitretin is more teratogenic than isotretinoin in the animal species studied to date, which is of special concern in view of the drug s prolonged elimination time (more than 3 months) after chronic administration. In cases where etretinate is formed by concomitant administration of acitretin and ethanol, etretinate may be found in plasma and subcutaneous fat for many years. 

Systemically administered retinoids such as isotretinoin (1, Accutane ) have several disadvantages such as a relatively narrow therapeutic index and a variety of toxic effects including teratogenicity. Topically administered retinoids may avoid some of those drawbacks. For instance, tazarotene (2, Tazorac ) is a topical receptor-selective retenoid that normalizes differentiation and proliferation of keratinocytes. Its major metabolite, tazarotenic acid (11), binds to retinoic acid receptors (RARs) with high affinity. 

Tazarotene (Tazorac) is an acetylenic retinoid prodrug that is hydrolyzed to its active form by an esterase. The active metabolite, tazarotenic acid, binds to retinoic acid receptors, resulting in modified gene expression. The precise mechanism of action in psoriasis is unknown but may relate to both anti-inflammatory and antiproliferative actions. Tazarotene is absorbed percutaneously, and teratogenic systemic concentrations may be achieved if applied to more than 20% of total body surface area. Women of childbearing potential must therefore be advised of the risk prior to initiating therapy, and adequate birth control measures must be utilized while on therapy. 

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