Retinoic acid metabolism blocking agents (RAMBAs): a new paradigm in the treatment of hyperkeratotic disorders

Verfaille, Christel J.; Borgers, M.; Steensel, M.A.M. van

doi:10.1111/j.1610-0387.2007.06541.x

Cited by 38 publications

(39 citation statements)

References 85 publications

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“…Retinoic acid metabolism blocking agents such as liarozole, which at present have an orphan drug status in the treatment of MeDOC, have shown an effectiveness equal to oral retinoids, and a favorable tolerability profile. [92][93][94] However, further clinical trials are needed to confirm these findings.…”

Section: Therapy and Implications Of Barrier Impairmentmentioning

confidence: 99%

Inherited ichthyoses/generalized Mendelian disorders of cornification

et al. 2012

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Section: Therapy and Implications Of Barrier Impairmentmentioning

confidence: 99%

Inherited ichthyoses/generalized Mendelian disorders of cornification

et al. 2012

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“…However, adverse effects of topical retinoids are quite frequent, and their severity is mild to moderate. Also, synthetic retinoids may stay in some organs for a long time, causing retinoid-related chronic toxicity and birth defects for months after discontinuation of therapy [28] . Unlike these existing therapies, the new RAMBA therapy modulates the body's own metabolism of ATRA to try to achieve the same therapeutic effects.…”

Section: Discussionmentioning

confidence: 99%

“…Because of its high selectivity for CYP26, adverse effects related to the use of talarozole are expected to be fewer and less severe than those reported for retinoids, making it a more suitable compound for therapy. In addition, there are indications that RAMBAs may have retinoid-independent effects on gene expression and lipid metabolism that contribute to their clinical effect [28] .…”

Section: Local Skin Pharmacokinetics Of Talarozolementioning

confidence: 99%

Local Skin Pharmacokinetics of Talarozole, a New Retinoic Acid Metabolism-Blocking Agent

Baert

Spiegeleer²

2011

Skin Pharmacol Physiol

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Talarozole is a new highly potent and selective azole derivative which inhibits cytochrome-P450-dependent all-trans-retinoic acid catabolism. It is in clinical development for the treatment of psoriasis and acne. However, no local pharmacokinetic data on the diffusion behaviour of talarozole in the skin itself are available. As topical application might be an interesting alternative to oral therapy because of the reduced systemic side effects, the aim of this study was to assess the transdermal behaviour of topically applied talarozole, including its within-skin distribution. Franz diffusion cell experiments with talarozole dissolved in different pharmaceutically relevant solvents (i.e. propylene glycol, oleolyl macrogol glyceride, isopropyl myristate, diethylene glycol monoethylether, ethanol, caprylic/capric triglyceride and caprylocaproyl macrogol glyceride) were performed to assess the transdermal behaviour of talarozole. Talarozole slightly diffused into the skin only when dissolved in propylene glycol, isopropyl myristate or ethanol. Although only 0.1% of the dose applied was found in the skin itself after 12–24 h, this was sufficient to achieve local concentrations well above the half-maximal inhibitory concentration value for talarozole. The distribution of talarozole within the skin was investigated: 80% was located in the epidermis, while the remaining 20% was found in the dermis. The epidermal concentration of talarozole achieved after a single topical application was sufficiently high to enable the potential induction of local retinoid-like effects.

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“…Retinoic acid signaling and altered retinoic acid concentrations play a role in various disease states (Miller, 1998;Kuenzli and Saurat, 2001;Njar, 2002;Ahmad and Mukhtar, 2004;Njar et al, 2006;Verfaille et al, 2008). As a result, the design and synthesis of inhibitors of CYP26 activity has received great interest in recent years.…”

Section: Introductionmentioning

confidence: 99%

Identification of Tazarotenic Acid as the First Xenobiotic Substrate of Human Retinoic Acid Hydroxylase CYP26A1 and CYP26B1

Foti¹,

Isoherranen²,

Zelter³

et al. 2016

The Journal of Pharmacology and Experimental Therapeutics

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Cytochrome P450 (CYP) 26A1 and 26B1 are heme-containing enzymes responsible for metabolizing all-trans retinoic acid (at-RA). No crystal structures have been solved, and therefore homology models that provide structural information are extremely valuable for the development of inhibitors of cytochrome P450 family 26 (CYP26). The objectives of this study were to use homology models of CYP26A1 and CYP26B1 to characterize substrate binding characteristics, to compare structural aspects of their active sites, and to support the role of CYP26 in the metabolism of xenobiotics. Each model was verified by docking at-RA in the active site and comparing the results to known metabolic profiles of at-RA. The models were then used to predict the metabolic sites of tazarotenic acid with results verified by in vitro metabolite identification experiments. The CYP26A1 and CYP26B1 homology models predicted that the benzothiopyranyl moiety of tazarotenic acid would be oriented toward the heme of each enzyme and suggested that tazarotenic acid would be a substrate of CYP26A1 and CYP26B1. Metabolite identification experiments indicated that CYP26A1 and CYP26B1 oxidatively metabolized tazarotenic acid on the predicted moiety, with in vitro rates of metabolite formation by CYP26A1 and CYP26B1 being the highest across a panel of enzymes. Molecular analysis of the active sites estimated the active-site volumes of CYP26A1 and CYP26B1 to be 918 Å 3 and 977 Å 3 , respectively. Overall, the homology models presented herein describe the enzyme characteristics leading to the metabolism of tazarotenic acid by CYP26A1 and CYP26B1 and support a potential role for the CYP26 enzymes in the metabolism of xenobiotics.

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Retinoic acid metabolism blocking agents (RAMBAs): a new paradigm in the treatment of hyperkeratotic disorders

Cited by 38 publications

References 85 publications

Inherited ichthyoses/generalized Mendelian disorders of cornification

Inherited ichthyoses/generalized Mendelian disorders of cornification

Local Skin Pharmacokinetics of Talarozole, a New Retinoic Acid Metabolism-Blocking Agent

Identification of Tazarotenic Acid as the First Xenobiotic Substrate of Human Retinoic Acid Hydroxylase CYP26A1 and CYP26B1

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