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Skin-targeted inhibition of PPAR β/δ by selective antagonists to treat PPAR β/δ-mediated psoriasis-like skin disease in vivo.

Hack K, Reilly L, Palmer C, Read KD, Norval S, Kime R, Booth K, Foerster J - PLoS ONE (2012)

Bottom Line: Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects.These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ.PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Institute, College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee, Scotland.

ABSTRACT
We have previously shown that peroxisome proliferator activating receptor ß/δ (PPAR β/δ is overexpressed in psoriasis. PPAR β/δ is not present in adult epidermis of mice. Targeted expression of PPAR β/δ and activation by a selective synthetic agonist is sufficient to induce an inflammatory skin disease resembling psoriasis. Several signalling pathways dysregulated in psoriasis are replicated in this model, suggesting that PPAR β/δ activation contributes to psoriasis pathogenesis. Thus, inhibition of PPAR β/δ might harbour therapeutical potential. Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects. Here, we report that three selective PPAR β/δ antagonists, GSK0660, compound 3 h, and GSK3787 can be formulated for topical application to the skin and that their skin concentration can be accurately quantified using ultra-high performance liquid chromatography (UPLC)/mass spectrometry. These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ. PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes. Significantly, the irreversible PPAR β/δ antagonist (GSK3787) retains efficacy when applied topically only three times per week which could be of practical clinical usefulness. Our data suggest that topical inhibition of PPAR β/δ to treat psoriasis may warrant further exploration.

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Low systemic absorption of topically applied PPAR β/δ antagonists.A. Peak blood concentrations of PPAR β/δ agonist GW501516, and antagonists GSK0660 and compound 3 h, respectively, at 1 h after topical application to skin. Left: Amount of drugs detected in systemic circulation, expressed as fraction of total amount applied, was calculated as detailed in methods. Right: Drug concentration expressed as molar concentration. B. GSK0660 concentration in blood (left) and total amount of circulating drug as fraction of amount applied (right, calculated as described in Methods) at the indicated time points after drug application. The horizontal dashed line represents the reported IC50 for GSK0660 acting on PPAR β/δ reported previously (300 nmol/L). Data shown represent average ± s.d. of n = 3 mice per data point.
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pone-0037097-g002: Low systemic absorption of topically applied PPAR β/δ antagonists.A. Peak blood concentrations of PPAR β/δ agonist GW501516, and antagonists GSK0660 and compound 3 h, respectively, at 1 h after topical application to skin. Left: Amount of drugs detected in systemic circulation, expressed as fraction of total amount applied, was calculated as detailed in methods. Right: Drug concentration expressed as molar concentration. B. GSK0660 concentration in blood (left) and total amount of circulating drug as fraction of amount applied (right, calculated as described in Methods) at the indicated time points after drug application. The horizontal dashed line represents the reported IC50 for GSK0660 acting on PPAR β/δ reported previously (300 nmol/L). Data shown represent average ± s.d. of n = 3 mice per data point.

Mentions: Targeting PPAR β/δ is potentially fraught with serious adverse effects, since PPAR β/δ impacts on a wide variety of metabolic processes. We developed a robust quantitative assay based on ULPC/mass spectrometry to allow quantification of GSK0660, as well as compound 3 h, in skin samples subjected to ointment treatment (see Methods). Using this technology, we investigated whether the topical application of PPAR β/δ antagonists to murine skin results in significant systemic drug accumulation. As shown in figure 2, peak systemic concentration of GSK0660, measured 1 h after topical application, remained well below reported EC50 and IC50 values while that of compound 3 h was slightly above the in vitro determined EC50 value at this time point (figure 1). The total amount of detectable compound was less than 0.01% of total drug applied. By contrast, the PPAR β/δ agonist used in this study, GW501516, exhibited 100-fold higher systemic absorption, achieving peak serum concentrations of 400 nM at 1 h post application, despite being concentrated 10-fold less (0.1% ointment). This concentration of GW501516 is well within the range of its expected pharmacological activity [20]. Pharmacokinetic measurements of GSK0660 in blood for 24 h after drug application showed no evidence of drug accumulation. Systemic concentration remained well below the predictive active concentration, and amounted to less than 0.01% of total drug applied being detectable (figure 2b). By contrast, the same amount of drug was able to achieve a high local concentration in skin, exhibiting a half life of approximately. 90 min (figure 3). These data demonstrate that topical administration of PPAR β/δ antagonists achieves skin specific drug application, thereby avoiding potential hazards associated with PPAR β/δ inhibition in other organ systems. Of note, since application of even 10-fold less concentrated agonist ointment (GW501516) achieves significant serum levels, only partial biological activity would be expected for the antagonists in this in vivo model.


Skin-targeted inhibition of PPAR β/δ by selective antagonists to treat PPAR β/δ-mediated psoriasis-like skin disease in vivo.

Hack K, Reilly L, Palmer C, Read KD, Norval S, Kime R, Booth K, Foerster J - PLoS ONE (2012)

Low systemic absorption of topically applied PPAR β/δ antagonists.A. Peak blood concentrations of PPAR β/δ agonist GW501516, and antagonists GSK0660 and compound 3 h, respectively, at 1 h after topical application to skin. Left: Amount of drugs detected in systemic circulation, expressed as fraction of total amount applied, was calculated as detailed in methods. Right: Drug concentration expressed as molar concentration. B. GSK0660 concentration in blood (left) and total amount of circulating drug as fraction of amount applied (right, calculated as described in Methods) at the indicated time points after drug application. The horizontal dashed line represents the reported IC50 for GSK0660 acting on PPAR β/δ reported previously (300 nmol/L). Data shown represent average ± s.d. of n = 3 mice per data point.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3351437&req=5

pone-0037097-g002: Low systemic absorption of topically applied PPAR β/δ antagonists.A. Peak blood concentrations of PPAR β/δ agonist GW501516, and antagonists GSK0660 and compound 3 h, respectively, at 1 h after topical application to skin. Left: Amount of drugs detected in systemic circulation, expressed as fraction of total amount applied, was calculated as detailed in methods. Right: Drug concentration expressed as molar concentration. B. GSK0660 concentration in blood (left) and total amount of circulating drug as fraction of amount applied (right, calculated as described in Methods) at the indicated time points after drug application. The horizontal dashed line represents the reported IC50 for GSK0660 acting on PPAR β/δ reported previously (300 nmol/L). Data shown represent average ± s.d. of n = 3 mice per data point.
Mentions: Targeting PPAR β/δ is potentially fraught with serious adverse effects, since PPAR β/δ impacts on a wide variety of metabolic processes. We developed a robust quantitative assay based on ULPC/mass spectrometry to allow quantification of GSK0660, as well as compound 3 h, in skin samples subjected to ointment treatment (see Methods). Using this technology, we investigated whether the topical application of PPAR β/δ antagonists to murine skin results in significant systemic drug accumulation. As shown in figure 2, peak systemic concentration of GSK0660, measured 1 h after topical application, remained well below reported EC50 and IC50 values while that of compound 3 h was slightly above the in vitro determined EC50 value at this time point (figure 1). The total amount of detectable compound was less than 0.01% of total drug applied. By contrast, the PPAR β/δ agonist used in this study, GW501516, exhibited 100-fold higher systemic absorption, achieving peak serum concentrations of 400 nM at 1 h post application, despite being concentrated 10-fold less (0.1% ointment). This concentration of GW501516 is well within the range of its expected pharmacological activity [20]. Pharmacokinetic measurements of GSK0660 in blood for 24 h after drug application showed no evidence of drug accumulation. Systemic concentration remained well below the predictive active concentration, and amounted to less than 0.01% of total drug applied being detectable (figure 2b). By contrast, the same amount of drug was able to achieve a high local concentration in skin, exhibiting a half life of approximately. 90 min (figure 3). These data demonstrate that topical administration of PPAR β/δ antagonists achieves skin specific drug application, thereby avoiding potential hazards associated with PPAR β/δ inhibition in other organ systems. Of note, since application of even 10-fold less concentrated agonist ointment (GW501516) achieves significant serum levels, only partial biological activity would be expected for the antagonists in this in vivo model.

Bottom Line: Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects.These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ.PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Institute, College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee, Scotland.

ABSTRACT
We have previously shown that peroxisome proliferator activating receptor ß/δ (PPAR β/δ is overexpressed in psoriasis. PPAR β/δ is not present in adult epidermis of mice. Targeted expression of PPAR β/δ and activation by a selective synthetic agonist is sufficient to induce an inflammatory skin disease resembling psoriasis. Several signalling pathways dysregulated in psoriasis are replicated in this model, suggesting that PPAR β/δ activation contributes to psoriasis pathogenesis. Thus, inhibition of PPAR β/δ might harbour therapeutical potential. Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects. Here, we report that three selective PPAR β/δ antagonists, GSK0660, compound 3 h, and GSK3787 can be formulated for topical application to the skin and that their skin concentration can be accurately quantified using ultra-high performance liquid chromatography (UPLC)/mass spectrometry. These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ. PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes. Significantly, the irreversible PPAR β/δ antagonist (GSK3787) retains efficacy when applied topically only three times per week which could be of practical clinical usefulness. Our data suggest that topical inhibition of PPAR β/δ to treat psoriasis may warrant further exploration.

Show MeSH
Related in: MedlinePlus