Plasma and Skin Concentration of 5-Methoxypsoralen in Psoriatic Patients After Oral Administration

Zucchi, A.; Raho, Ersilia; Marconi, Bettina; Nicoli, Sara; Santini, Marcello; Allegra, F; Colombo, Paolo; Bettini, Ruggero; Santi, Patrizia

doi:10.1046/j.0022-202x.2001.01419.x

Cited by 17 publications

(22 citation statements)

References 14 publications

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“…In addition, many systemically administered drugs distribute into the skin, with local exposure approaching (Klimowicz et al, 1988;Borg et al, 1999;Krishna et al, 2010), or sometimes even exceeding, corresponding plasma levels (Zucchi et al, 2001;Brunner et al, 2002). As a result, cutaneous drug metabolism is relevant for pharmacotherapy, both from the perspectives of metabolic elimination and activation of prodrugs, as well as the formation of reactive metabolites that may cause skin toxicity (Sharma et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

et al. 2014

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Although skin is the largest organ of the human body, cutaneous drug metabolism is often overlooked, and existing experimental models are insufficiently validated. This proof-of-concept study investigated phase II biotransformation of 11 test substrates in fresh full-thickness human skin explants, a model containing all skin cell types. Results show that skin explants have significant capacity for glucuronidation, sulfation, N-acetylation, catechol methylation, and glutathione conjugation. Novel skin metabolites were identified, including acyl glucuronides of indomethacin and diclofenac, glucuronides of 17b-estradiol, N-acetylprocainamide, and methoxy derivatives of 4-nitrocatechol and 2,3-dihydroxynaphthalene. Measured activities for 10 mM substrate incubations spanned a 1000-fold: from the highest 4.758 pmol·mg skin ·h -1 for 17b-estradiol 17-glucuronidation. Interindividual variability was 1.4-to 13.0-fold, the highest being 4-methylumbelliferone and diclofenac glucuronidation. Reaction rates were generally linear up to 4 hours, although 24-hour incubations enabled detection of metabolites in trace amounts. All reactions were unaffected by the inclusion of cosubstrates, and freezing of the fresh skin led to loss of glucuronidation activity. The predicted whole-skin intrinsic metabolic clearances were significantly lower compared with corresponding whole-liver intrinsic clearances, suggesting a relatively limited contribution of the skin to the body's total systemic phase II enzymemediated metabolic clearance. Nevertheless, the fresh full-thickness skin explants represent a suitable model to study cutaneous phase II metabolism not only in drug elimination but also in toxicity, as formation of acyl glucuronides and sulfate conjugates could play a role in skin adverse reactions.

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Section: Introductionmentioning

confidence: 99%

Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

et al. 2014

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“…5-MOP gel formulation and application time, able to produce in vitro drug concentration profiles similar to those previously obtained in vivo, after oral administration of 5-MOP, and considered therapeutically active [10].…”

Section: In Vitro Accumulation In Human Skinmentioning

confidence: 51%

“…The influence of gel composition and application time was studied in vitro. Then, 5-MOP distribution was measured in vivo in healthy and psoriatic sites of psoriatic patients, after topical application, and compared with the skin distribution data previously obtained after oral administration [10].…”

Section: -Or 8-methoxypsoralen (5-mop 8-mop)mentioning

confidence: 99%

“…The mobile phase was methanol-water (65:35) at a flow rate of 0.8 ml/min, and the wavelength was set at 300 nm. The method was validated according to USP24 [10]. The limit of quantification was 0.05 ng/ml.…”

Section: -Mop Analysismentioning

confidence: 99%

“…Drug extraction and analysis from skin biopsies were performed according to Zucchi et al [10]. Briefly, the 4-mm diameter skin biopsies were frozen in liquid nitrogen and horizontally cut using a cryomicrotome (Miles, Elkhart, Ind., USA).…”

Section: -Mop Analysismentioning

confidence: 99%

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In vitro and in vivo Study of 5-Methoxypsoralen Skin Concentration after Topical Application

Colombo¹,

Zucchi

Allegra

et al. 2003

Skin Pharmacol Physiol

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The aim of this work was to study the skin distribution of 5-methoxypsoralen (5-MOP) after application of topical gels, in vitro and in vivo, in both healthy and psoriatic skin sites of 6 psoriatic patients. Drug skin distribution was determined using the thin slicing technique and subsequent HPLC analysis. In the presence of dermatological disease, i.e. psoriasis, the permeability of the tissue changed considerably, leading to an important increase in the cumulative amount of 5-MOP recovered in the skin after topical application. The amount of 5-MOP found in vitro in the human skin was intermediate between those cumulated in healthy and psoriatic skin sites during an in vivo experiment. The gel formulation is an efficacious carrier for the topical photochemotherapy of psoriasis with 5-MOP, since it allows drug penetration in psoriatic skin.

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Effects of Furanocoumarins from Apiaceous Vegetables on the Catalytic Activity of Recombinant Human Cytochrome P-450 1A2

et al. 2011

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Inhibition of cytochrome P-450 1A2 (CYP1A2)-mediated activation of procarcinogens may be an important chemopreventive mechanism. Consumption of apiaceous vegetables (rich in furanocoumarins) inhibits CYP1A2 in humans. Because many furanocoumarins are potent inhibitors of several CYP, we characterized the effects of three furanocoumarins from apiaceous vegetables on human CYP1A2 (hCYP1A2). We assessed hCYP1A2 methoxyresorufin O-demethylase (MROD) activity using microsomes from Saccharomyces cerevisiae expressing hCYP1A2. Isopimpinellin exhibited mechanism-based inactivation (MBI) of hCYP1A2 (Ki = 1.2 μM, kinact = 0.34 min−1, and partition ratio = 8). Imperatorin and trioxsalen were characterized as mixed inhibitors with Ki values of 0.007 and 0.10 μM, respectively. These results indicate that even if present at low levels in apiaceous vegetables, imperatorin, trioxsalen and isopimpinellin may contribute significantly to CYP1A2 inhibition and potentially decreased procarcinogen activation. Moreover, the in vivo effect of isopimpinellin on CYP1A2 may be longer lasting compared to reversible inhibitors.

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Plasma and Skin Concentration of 5-Methoxypsoralen in Psoriatic Patients After Oral Administration

Cited by 17 publications

References 14 publications

Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

In vitro and in vivo Study of 5-Methoxypsoralen Skin Concentration after Topical Application

Effects of Furanocoumarins from Apiaceous Vegetables on the Catalytic Activity of Recombinant Human Cytochrome P-450 1A2

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