Effects of Skin Metabolism on Percutaneous Penetration of Lipophilic Drugs

Bando, Hiroto; Mohri, Saya; Yamashita, Fumiyoshi; Takakura, Yoshinobu; Hashida, Mitsuru

doi:10.1021/js960408n

Cited by 86 publications

(56 citation statements)

References 13 publications

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“…In fact, increased plasma levels of E 1 and estrogen overloading the liver changing protein synthesis due to oral E 2 replacement have been suspected to be a reason for adverse effects [10,14]. Besides influencing the E 2 /E 1 ratio in plasma, cutaneous E 2 metabolism may also influence permeation/penetration of the native entity, since metabolites with different physicochemical properties distribute independently from native drug [24].…”

Section: Discussionmentioning

confidence: 99%

Cutaneous Estradiol Permeation, Penetration and Metabolism in Pig and Man

Mahmoud

Haberland²,

Dürrfeld³

et al. 2004

Skin Pharmacol Physiol

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Aim and Methods: Drug development in dermatotherapy and also development of transdermal therapeutic systems (TTS) demand high-predictive in vitro models to estimate drug levels in skin and systemic uptake. Here we compare three ready-to-use models, reconstructed human epidermis, split porcine skin and the perfused porcine forelimb. 17β-Estradiol (E₂), which is highly metabolized by skin cells, serves as model drug since E₂ application is of high relevance in hormone replacement therapy while topical E₂ may promote wound healing. E₂ TTS, gel and an ethanolic solution were investigated for cutaneous penetration, permeation and metabolism. Results: E₂ TTS enabled an E₂ uptake of 42.9% of the applied dose accompanied by a high percentage of E₂ metabolism (30% of the penetrated dose) in the perfused porcine forelimb. In Franz cell experiments with reconstructed human epidermis and split porcine skin, the gel allowed an E₂ uptake of 41.7 and 22.9% of the applied dose accompanied by a high E₂ metabolism (42.6 and 28.6% of the penetrated dose). Due to toxic effects of the vehicle, this was not true with an ethanolic solution, then E₂ permeation and metabolism were clearly diminished. Most importantly, the in vitro models proved to be predictive with respect to the E₂/estrone ratio in female plasma under transdermal hormone replacement therapy. Conclusion: In vitro tests should reduce the need for both animal and human studies for cutaneous uptake and metabolism in the future.

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Section: Discussionmentioning

confidence: 99%

Cutaneous Estradiol Permeation, Penetration and Metabolism in Pig and Man

Mahmoud

Haberland²,

Dürrfeld³

et al. 2004

Skin Pharmacol Physiol

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“…Similarly, the EC Scienti¼c Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food of the European Food Safety Authority (EFSA) reviewed propylparaben (EFSA, 2004) and was unable to establish a no-observed-adverse-effect-level for reproductive and endocrine toxicity, and consequently an ADI, effectively recommending its exclusion/withdrawal from food use. These regulatory evaluations involve oral exposures but it has been previously suggested that dermal application of paraben esters may represent a special case because of a higher probability of escaping limited skin esterase action (Bando et al, 1997;Oh et al, 2002;Prusakiewicz et al, 2006;El Hussein et al, 2007;Harville et al, 2007;Janjua et al, 2007) and local subcutaneous tissue accumulation (see Harvey and Darbre, 2004), indicating a need for regulatory risk assessment harmonization. Harmonization would require withdrawal of butylparaben and propylparaben from cosmetics.…”

Section: Regulatory Status Of Parabensmentioning

confidence: 99%

“…Parabens are known to be readily absorbed through the skin and it has been suggested that hydrolysis of parabens by skin esterases could be incomplete in the context of increasing cosmetic useage and inter-individual variations (Darbre et al, 2004a;Harvey and Darbre, 2004). In vitro studies have shown that 30% of applied propylparaben penetrates the skin intact in rat skin (Bando et al, 1997), and after 8 h contact, penetration of some esters can be even higher with up to 60% of methylparaben and 40% of ethylparaben crossing rabbit skin intact (Pedersen et al, 2007). In humans, variations between individuals in hydrolysis of parabens have now been shown in the case of human liver esterases (Jewell et al, 2007), although studies are still lacking for skin esterases.…”

Section: Introductionmentioning

confidence: 99%

Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion of potential human health risks

Darbre

Harvey

2008

J of Applied Toxicology

604

375

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This toxicology update reviews research over the past four years since publication in 2004 of the ¼rst measurement of intact esters of p-hydroxybenzoic acid (parabens) in human breast cancer tissues, and the suggestion that their presence in the human body might originate from topical application of bodycare cosmetics. The presence of intact paraben esters in human body tissues has now been con¼rmed by independent measurements in human urine, and the ability of parabens to penetrate human skin intact without breakdown by esterases and to be absorbed systemically has been demonstrated through studies not only in vitro but also in vivo using healthy human subjects. Using a wide variety of assay systems in vitro and in vivo, the oestrogen agonist properties of parabens together with their common metabolite ( p-hydroxybenzoic acid) have been extensively documented, and, in addition, the parabens have now also been shown to possess androgen antagonist activity, to act as inhibitors of sulfotransferase enzymes and to possess genotoxic activity. With the continued use of parabens in the majority of bodycare cosmetics, there is a need to carry out detailed evaluation of the potential for parabens, together with other oestrogenic and genotoxic co-formulants of bodycare cosmetics, to increase female breast cancer incidence, to interfere with male reproductive functions and to in½uence development of malignant melanoma which has also recently been shown to be in½uenced by oestrogenic stimulation.

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“…Parabens applied to skin are known to be partly metabolised by four carboxyl esterases capable of hydrolysing the different parabens to phydroxybenzoic acid (Lobemeier et al 1996). However, in vitro studies on penetration of rat skin by butylparaben and propylparaben indicated that 4% of butylparaben and 30% of propylparaben were not hydrolysed (Bando et al 1997). In view of the oestrogenic properties documented by Routledge et al (1998) and the present work, more data are clearly needed on the systemic exposure of humans to this group of preservatives.…”

Section: Resultsmentioning

confidence: 68%

The Preservatives Ethyl‐, Propyl‐ and Butylparaben are Oestrogenic in an in vivo Fish Assay

Pedersen

Christiansen

et al. 2000

Pharmacology & Toxicology

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Abstract:The widely used phenolic preservatives ethylparaben, propylparaben, butylparaben and their common metabolite p-hydroxybenzoic acid were tested for their ability to evoke an oestrogenic response in vivo. Yolk protein induction in sexually immature rainbow trout was used as an oestrogen-specific endpoint after repeated injections of the compounds. All tested parabens were oestrogenic in doses between 100 and 300 mg/kg, while the metabolite showed no activity. Ethylparaben was found to be approximately sixty times weaker than propyl-and butylparaben which had oestrogenic potencies comparable to those previously found for bisphenol A.Chemicals known to mimic the steroid hormone oestrogen are structurally diverse, although some of the most potent i.e. alkylphenols (Routledge & Sumpter 1997) and bisphenol A (Gaido et al. 1997) share a para-substituted phenol as a common molecular feature. Another class of para-substituted phenols is the food and cosmetic preservatives alkyl hydroxybenzoates (alkylparabens). In a survey of 215 cosmetic products, methyl-, ethyl-, n-propyl-and n-butylparaben were detected in 98, 32, 38 and 16% respectively of the products (Rastogi et al. 1995). Parabens are often used in combinations rather than singly to ensure the most optimal preservation of the cosmetic products (Dal Pozzo & Pastori 1996). Furthermore, parabens are widely used as preservatives in several food and beverage products (Elder 1984). In an in vitro test system methyl-, ethyl-, n-propyl-and nbutylparaben were all found to be weakly oestrogenic (Routledge et al. 1998). In the same study methyl-and nbutylparaben were tested in a rat uterotrophic assay, but only n-butylparaben showed oestrogenic activity (Routledge et al. 1998). Using a similar test system a common metabolite of parabens, p-hydroxy-benzoic acid, has previously been reported to have oestrogenic effects (Lemini et al. 1997).A diverse range of screening systems by which oestrogenicity can be demonstrated is currently used, including in vivo induction of the yolk precursor protein vitellogenin in oviparous animals (Sumpter & Jobling 1995;Palmer & Palmer 1995;Palmer et al. 1998). The present paper describes the in vivo hazard identification of the oestrogenicity of p-hydroxybenzoate and ethyl-, n-propyl-and n-butylparaben using vitellogenin induction in rainbow trout as a test system. Author for correspondence: Poul Bjerregaard, Institute of Biology, USD, Odense University, Campusvej 55, DK-5230 Odense M, Denmark (fax π45 6593 0457, e-mail poul/biology.sdu.dk). Materials and MethodsExposure of animals. Juvenile rainbow trout (80-120 g) were kept under a photoperiod of 12 hr light:12 hr dark in 80 l steel tanks supplied with running freshwater. After an acclimation period of one week the fish were given an intraperitoneal injection of the compounds to be tested. Prior to injections and blood samplings, the fish were anaesthetizised with 0.02 % phenoxyethanol. All injection volumes were adjusted to 1 ml/kg fish. Groups of six or ten fish each were injected a...

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Effects of Skin Metabolism on Percutaneous Penetration of Lipophilic Drugs

Cited by 86 publications

References 13 publications

Cutaneous Estradiol Permeation, Penetration and Metabolism in Pig and Man

Cutaneous Estradiol Permeation, Penetration and Metabolism in Pig and Man

Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion of potential human health risks

The Preservatives Ethyl‐, Propyl‐ and Butylparaben are Oestrogenic in an in vivo Fish Assay

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