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At least 73 records · Page 4Linked to original sources
PubMed1987

Skin absorption and cutaneous first pass metabolism of topical steroids: in vitro studies with mouse skin in organ culture.

Using mouse skin maintained in a permeability chamber-organ culture system, we have examined the percutaneous penetration and cutaneous fate of some selected steroids. At 16 hr after in vitro topical application (10 micrograms/2 cm2), the extent of permeation of the selected steroids was testosterone (65.13%) much greater than cortisol (18.1%) = estradiol (18.0%) greater than estrone (10.58%) much greater than estriol (2.45%). Permeation was accompanied by cutaneous first pass metabolism. In addition to water-soluble metabolites, other metabolites found in the perfusion medium from topical testosterone included 5 alpha-dihydrotestosterone, 5 alpha-androstanedione and androstenedione. Cortisone was identified as one of the metabolites of topical cortisol. For the estrogens, estradiol and estriol were metabolites of topical estrone, whereas estrone and estriol were metabolites of topical estradiol. The extent of cutaneous first pass metabolism of these selected steroids varies considerably. Estrone was metabolized extensively, but only limited metabolism of estradiol and cortisol was observed during their translocation through the skin. With testosterone, it was evident that an increase in the topically applied dose was accompanied by a decrease in the relative extent of both permeation and cutaneous first pass metabolism. However, cutaneous first pass metabolism of estriol was essentially negligible. These observations demonstrated that both diffusional and metabolic processes are important in the percutaneous fate of topical steroids. They also suggest that in future studies concerned with the absorption and bioavailability of topically applied chemicals, an assessment of the drug-metabolizing capabilities of the skin needs to be considered.

Administration, Cutaneous↗
PubMed2006

Reconstructed human epidermis for skin absorption testing: results of the German prevalidation study.

Exposure to chemicals absorbed by the skin can threaten human health. In order to standardise the predictive testing of percutaneous absorption for regulatory purposes, the OECD adopted guideline 428, which describes methods for assessing absorption by using human and animal skin. In this study, a protocol based on the OECD principles was developed and prevalidated by using reconstructed human epidermis (RHE). The permeation of the OECD standard compounds, caffeine and testosterone, through commercially available RHE models was compared to that of human epidermis and animal skin. In comparison to human epidermis, the permeation of the chemicals was overestimated when using RHE. The following ranking of the permeation coefficients for testosterone was obtained: SkinEthic > EpiDerm, EPISKIN > human epidermis, bovine udder skin, pig skin. The ranking for caffeine was: SkinEthic, EPISKIN > bovine udder skin, EpiDerm, pig skin, human epidermis. The inter-laboratory and intra-laboratory reproducibility was good. Long and variable lag times, which are a matter of concern when using human and pig skin, did not occur with RHE. Due to the successful transfer of the protocol, it is now in the validation process.

Adult↗
PubMed2004

The significance of in vitro rat skin absorption studies to human risk assessment.

The present paper reviews the comparative rates of skin penetration between rat and man for a total of 14 chemicals in in vitro absorption studies. The results showed that in vitro absorption assays are capable of demonstrating large differences in the rate of skin penetration. Saturation of absorption was also frequently observed at higher exposure levels. The highest absorption rates through rat and human epidermis were observed with compounds with a molecular weight of approximately 300, an aqueous solubility of approximately 1-6 mg/l, and a log10 (P(OCTANOL/WATER)) of approximately 3-4. When the absorption data for 3 compounds with a log10 (P(OCTANOL/WATER)) of 2.9-3.0 were compared, there appeared to be an inverse relationship between molecular weight/aqueous solubility and the rate of dermal absorption. Lipophilic compounds with low aqueous solubility (<4 mg/l) showed the highest penetration rates through rat skin, but this was not always the case for human skin. The human skin was invariably less permeable to all tested substances than rat skin, though no constant factor of difference could be identified. The factor of difference would not appear to be determined by molecular weight, lipophilicity, or aqueous solubility. The actual systemic exposure of humans may be significantly overestimated if risk assessment is based only on the results of an in vivo rat study. It would appear that dermal penetration through human skin should be based on the combined use of in vivo and in vitro data, using the following equation: %Human dermal penetration= [[% dermal penetration rat (in vivo)] x [rate dermal penetration human (in vitro)]] / [rate dermal penetration rat (in vitro)]

Animals↗
PubMed2000

Human skin absorption and metabolism of the contact allergens, cinnamic aldehyde, and cinnamic alcohol.

trans-Cinnamaldehyde and trans-cinnamic alcohol have been commonly reported to cause allergic contact dermatitis (ACD) in humans. Cinnamaldehyde is a more potent skin sensitizer than cinnamic alcohol. It has been hypothesized that cinnamic alcohol is a "prohapten" that requires metabolic activation, presumably by oxidoreductase enzymes such as alcohol dehydrogenase (ADH) or cytochrome P450 2E1 (CYP2E1), to the protein-reactive cinnamaldehyde (a hapten). In this study, the in vitro percutaneous absorption and metabolism of cinnamaldehyde and cinnamic alcohol (78 micromol dose) has been examined using freshly excised, metabolically viable, full-thickness breast and abdomen skin from six female donors. Penetration rates and total cumulative recoveries of cinnamic compounds that were present in receptor fluid, extracted from within the skin, evaporated from the skin surface, or remained unabsorbed on the skin surface after 24 h were quantified by reversed-phase high-performance liquid chromatography. Biotransformation of cinnamaldehyde to both cinnamic alcohol and cinnamic acid was observed. Topically applied cinnamic alcohol was converted to cinnamaldehyde (found on the skin surface only) and cinnamic acid. To establish whether these biotransformations were enzymatic, experiments were performed in the absence and presence of varying concentrations (80-320 micromol) of the ADH/CYP2E1 inhibitors pyrazole or 4-methylpyrazole. The observation that pyrazole significantly reduced (p < 0.05) the total penetration of cinnamic metabolites into receptor fluid, following either cinnamaldehyde or cinnamic alcohol treatment, but did not significantly affect parent chemical penetration, suggests that we are measuring cutaneous metabolic products of ADH activity. The skin absorption and metabolism of cinnamaldehyde and cinnamic alcohol will play an important role in the manifestation of ACD following topical exposure to these compounds.

Acrolein↗
PubMed1991

Enhancement of propranolol hydrochloride and diazepam skin absorption in vitro: effect of enhancer lipophilicity.

The enhancement of model hydrophilic (propranolol hydrochloride) and lipophilic (diazepam) drug penetration across rat and hairless mouse skin in vitro has been studied. Preliminary experiments established that most n-alkanes having chain lengths of between 7 and 16 promote the flux of both drugs. For propranolol, enhancement varied parabolically with carbon number; for diazepam, heptane was ineffective and all others were essentially equipotent. Enhancement by n-nonane was then compared with that by n-nonanol. Propranolol flux was increased by both enhancers, whereas diazepam penetration was not affected by the less lipophilic alcohol. The enhancement of propranolol by n-nonane and n-nonanol was examined as a function of adjuvant concentration in the applied formulation. Maximum increases in maximum penetration rates of 6.5-fold (n-nonane) and 8.2-fold (n-nonanol) were determined. As expected, the enhancement was saturable, indicative of a maximally perturbed stratum corneum. Finally, the penetration enhancing abilities of six monoterpenes were assessed. The purely hydrocarbon analogues promoted both propranolol and diazepam transport to an extent similar to that of n-nonane. The terpenes with hydrogen-bonding ability, however, only enhanced propranolol flux (at a level comparable to n-nonanol). While the data reported do not directly reveal mechanistic information on percutaneous penetration enhancement, they do provide a starting point for the rational investigation of interrelationships between drug, enhancer, and skin. Such information is clearly essential for the optimization and exploitation of transdermal drug delivery.

Alkanes↗
PubMed2002

Skin absorption and human risk assessment.

A common practice is to assume that percutaneous absorption does not significantly contribute to total bioavailability and therefore, absorption through other routes is more important to human risk assessment. The skin can represent a significant barrier to absorption, but some substances are absorbed to a significant extent. Since there is a potential for percutaneous penetration that is not consistent between species or substances, the assessment of the potential contribution of total body burden from dermal exposures should be considered. This review briefly discusses some theories, practices, and factors that affect percutaneous absorption with an emphasis on how percutaneous absorption evaluations apply to human risk assessment.

Animals↗