RESUMO
The in vitro percutaneous absorption of carbon-14-labeled benzene ([(14)C]benzene) in dermatomed human skin was determined using 2 cleaning products containing benzene. This study utilized cleaning solutions commonly used in the workplace. As Environmental Protection Agency (EPA) guidelines cover dose occlusion for volatile chemicals, the treatments were both nonoccluded and occluded, with low (10 microL/cm(2)), high (30 microL/cm(2)), and multiple (10 microL/cm(2) x 3 at 0, 30, and 60 min) doses. In an open-to-air test, the benzene quickly evaporated, and only 0.5%-1.4% of the original dose remained after 30 minutes. In the diffusion studies, human skin absorption of benzene peaked in the first few hours without occlusion, but was sustained for 24 hours with occlusion. The absorption of a high single dose was 1.2 +/- 0.16 times (mean +/- standard deviation) greater than that of a multiple dose, whereas theory would predict 1.0. The low-dose to high- or multiple-dose ratio was 3.6 +/- 2.2, so there was a clear dose response. The effect of occlusion was significant. In this study occlusion increased absorption by 40.1 +/- 24.6 times. These data place into partial perspective the role of occlusion in benzene flux, but should not be generalized until other volatile substances are studied in the experimental system and further validated with in vivo systems.
Assuntos
Benzeno/farmacocinética , Detergentes/farmacocinética , Exposição Ocupacional/análise , Absorção Cutânea , Pele/efeitos dos fármacos , Administração Tópica , Benzeno/química , Radioisótopos de Carbono , Detergentes/química , Humanos , Técnicas In Vitro , Pele/metabolismo , VolatilizaçãoRESUMO
Regulatory agencies have relied on dermal absorption data for soluble forms of arsenic as the technical basis for specific absorption values that are used to calculate exposure to arsenic in weathered soil. These evaluations indicate that percutaneous absorption of arsenic from soil ranges from 3.2 to 4.5% of the dermally applied dose, based on studies of arsenic freshly mixed with soil. When this value is incorporated into risk assessments and combined with other assumptions about dermal exposures to soil, the conclusion is often that dermal exposure to arsenic from soil may contribute significantly to overall exposure to arsenic in soil. Prior characterization research has indicated that the solubility of arsenic in soil varies, depending on the provenance of the soil, the source of the arsenic, and the chemical interaction of arsenic with other minerals present within the soil matrix. Weathering produces forms of arsenic that are more tightly bound within the soil and less available for absorption. Our research expands on prior in vivo studies to provide insights into the potential for dermal absorption of arsenic from the more environmentally relevant substrate of soil. Specifically, two soils with very high concentrations of arsenic were evaluated under two levels of skin hydration. One soil, containing 1400 mg/kg arsenic, was collected adjacent to a pesticide production facility in New York. The other soil, containing 1230 mg/kg arsenic, was collected from a residential area with a history of application of arsenical pesticides. Although the results of this research are constrained by the small study size dictated by the selection of an animal research model using monkeys, the statistical power was optimized by using a "crossover" study design, wherein each animal could serve as its own comparison control. No other models (animal or in vitro) were deemed adequate for studying the dermal absorption of soil arsenic. Our results show dermal absorption of soluble arsenic in solution to be 4.8 +/- 5.5%, which is similar to results reported earlier for arsenic in solution (and used by regulatory agencies in recommendations regarding dermal absorption of arsenic). Conversely, absorption following application of arsenic in the soil matrices resulted in mean estimated arsenic absorption of 0.5% or less for all soils, and all individual estimates were less than 1%. More specifically, following application of arsenic-bearing soils to the abdomens of monkeys, urinary arsenic excretion could not be readily distinguished from background. This was true across all five soil-dosing trials, including application of the two dry soils and three trials with wet soil. These findings are consistent with our understanding of the environmental chemistry of arsenic, wherein arsenic can be present in soils in complexed mineral forms. This research addresses an important component involved in estimating the true contribution of percutaneous exposures to arsenic in soil relative to exposures via ingestion. Our findings suggest that dermal absorption of arsenic from soil is truly negligible, and that EPA's current default assumption of 3% dermal absorption of arsenic from soils results in significant overestimates of exposure.
Assuntos
Arsênio/farmacocinética , Macaca mulatta/metabolismo , Absorção Cutânea , Poluentes do Solo/farmacocinética , Administração Cutânea , Animais , Arsênio/urina , Disponibilidade Biológica , Feminino , Metais/análise , Medição de Risco , Solo/análise , Poluentes do Solo/urinaRESUMO
Onychomycosis is a challenging fungal infection to treat topically, likely due to the unique properties of the nail plate. This seemingly impenetrable barrier has high resistance to the passage of antifungal drugs in sufficient concentrations to kill the causative fungi deep in the nail bed. Recently, a new class of antifungal agent was described, termed oxaboroles, which have broad-spectrum activity. These oxaboroles were designed with properties believed to be required to allow for easier transit through the nail plate. Herein, we report (i) the nail penetration results of four oxaboroles that led to the selection of AN2690, (ii) the results of the nail penetration of AN2690 from four vehicles, and (iii) the nail penetration of AN2690 in its chosen vehicle compared to a commercial control, ciclopirox. AN2690 has superior penetration compared to ciclopirox, and achieves levels within and under the nail plate that suggest it has the potential to be an effective topical treatment for onychomycosis.
Assuntos
Antifúngicos/metabolismo , Compostos de Boro/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Unhas/metabolismo , Antifúngicos/química , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Compostos de Boro/química , Compostos de Boro/farmacologia , Compostos de Boro/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Química Farmacêutica , Ciclopirox , Difusão , Cultura em Câmaras de Difusão , Composição de Medicamentos , Etanol/química , Dermatoses da Mão/tratamento farmacológico , Humanos , Estrutura Molecular , Onicomicose/tratamento farmacológico , Permeabilidade , Veículos Farmacêuticos/química , Projetos Piloto , Propilenoglicol/química , Piridonas/metabolismo , Solubilidade , Fatores de TempoRESUMO
This study determined the in vivo human bioavailability of topical estradiol, and the transfer of drug between dosed subject and naive recipient. In vivo bioavailability was determined in human volunteers by (14)C urinary excretion following topical [(14)C]-estradiol (0.06%) dose administration and were adjusted by intravenous human excretion amounts to give absolute bioavailability amounts. Drug transfer was determined by volunteer skin contact/rubbing for 15 minutes, 1 hour after topical dosing. [(14)C]-estradiol bioavailability as percent dose absorbed (n=6) was 7.5+/-4.1 from protected dose site, 8.2+/-6.3 from non-protected dose site, 6.6+/-7.6 from dosed volunteers subjected to skin contact/rub and 4.3+/-3.8 from non-dosed volunteers subjected to skin contact/rub. Between these small groups, the values were not statistically different. Under experimental conditions, a measurable dose of radioactive 17beta-estradiol dose was delivered to naive recipient volunteers through skin contact/rub with other volunteers previously topically dosed. Any residual topical bioactive chemical which resides on the open skin surface can transfer by skin contact to another individual. It is important for prescribing physicians and patients to understand that clinically significant transfer of topical bioactive drugs can occur. This may be particularly important for substances which may produce inadvertent effects.
Assuntos
Estradiol/farmacocinética , Absorção Cutânea , Administração Tópica , Adulto , Idoso , Disponibilidade Biológica , Estradiol/administração & dosagem , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Current knowledge of percutaneous absorption of arsenic is based on studies of rhesus monkeys using soluble arsenic in aqueous solution, and soluble arsenic mixed with soil (Wester et al., 1993). These studies produced mean dermal absorption rates in the range of 2.0-6.4% of the applied dose. Subsequently, questions arose as to whether these results represent arsenic absorption from environmental media. Factors such as chemical interactions, the presence of other metals, and the effects of weathering on environmental media all can affect the nature of arsenic and its potential for percutaneous absorption. Therefore, research specific to more relevant matrices is important. The focus of this effort is to outline study design considerations, including particle size, application rates, means of ensuring skin contact and appropriate statistical evaluation of the data. Appropriate reference groups are also important. The potential for background exposure to arsenic in the diet possibly obscuring a signal from a dermally applied dose of arsenic will also be addressed. We conclude that there are likely to be many site- or sample-specific factors that will control the absorption of arsenic, and matrix-specific analyses may be required to understand the degree of percutaneous absorption.
Assuntos
Arsênio/farmacocinética , Absorção Cutânea , Administração Tópica , Animais , Arsênio/urina , Disponibilidade Biológica , Poluentes Ambientais/farmacocinética , Feminino , Macaca mulatta , Tamanho da Partícula , Medição de Risco , Poluentes do Solo/farmacocinéticaRESUMO
The human nail penetration of the antifungal ciclopirox was determined for marketed gel containing 0.77% of ciclopirox, an experimental gel containing 2% of ciclopirox, and a marketed lacquer containing 8% of ciclopirox. After 14 days dosing, unabsorbed drug remaining on the surface, drug within the infection-prone area, and the amount that had penetrated through the nail were determined. Ciclopirox delivery into and through the nail was significantly greater from the marketed gel, than from either the experimental gel or the nail lacquer (p < 0.05). In addition, the surface nail contained more unabsorbed drug from the lacquer. Further, the drug penetrating into and through the nail was also greater from the marketed gel, leading to a higher Calculated Efficacy Coefficient for the marketed gel, than from the marketed lacquer or the experimental gel. The formulation plays an important role in the enhancement of ciclopirox permeation into and through the human nail plate, and the concentration of ciclopirox in the formulation was not a factor in determining penetration.
Assuntos
Antifúngicos/farmacocinética , Unhas/metabolismo , Piridonas/farmacocinética , Adjuvantes Farmacêuticos/farmacologia , Antifúngicos/administração & dosagem , Antifúngicos/química , Transporte Biológico , Ciclopirox , Relação Dose-Resposta a Droga , Excipientes/farmacologia , Géis , Humanos , Técnicas In Vitro , Piridonas/administração & dosagem , Piridonas/químicaRESUMO
This study was conducted to evaluate the dermal absorption of arsenic from residues present on the surface of wood preserved with chromated copper arsenate (CCA). The research reported herein used methods parallel to those of earlier research on the dermal absorption of radiolabeled arsenic (R. C. Wester et al., 1993, Fund. Appl. Toxicol. 20, 336-340), with modifications to allow use of environmental matrices that are not radiolabeled. These modifications include the surface area of application and dietary intake of arsenic, thus maximizing the potential for detection of dermally absorbed arsenic in exposed animals above diet-associated background levels of exposure. Two forms of arsenic were administered in this work. The first, arsenic in solution, was applied to the skin of monkeys to calibrate the model against prior absorption research and to serve as the basis of comparison for absorption of arsenic from CCA-treated wood residues. The second substrate was residue that resides on the surface of CCA-treated wood. Results from this research indicate that this study methodology can be used to evaluate dermally absorbed arsenic without the use of a radiolabel. Urinary excretion of arsenic above background levels can be measured following application of soluble arsenic, and absorption rates (0.6-4.4% absorption) are consistent with prior research using the more sensitive, radiolabeled technique. Additionally, the results show that arsenic is poorly absorbed from CCA-treated wood residues (i.e., does not result in urinary arsenic excretion above background levels).
Assuntos
Arseniatos/farmacocinética , Arsênio/farmacocinética , Poluentes Ambientais/farmacocinética , Resíduos de Praguicidas/farmacocinética , Absorção Cutânea , Administração Tópica , Animais , Arseniatos/química , Arsênio/análise , Arsênio/urina , Cromo/análise , Cobre/análise , Poluentes Ambientais/análise , Poluentes Ambientais/urina , Feminino , Macaca mulatta , Modelos Animais , Resíduos de Praguicidas/análise , Soluções , Água , MadeiraRESUMO
This study determines the enhancing effects of 2-n-nonyl-1,3-dioxolane on the penetration of econazole, an antifungal drug, into the deeper layers of the human nail where fungal infection resides. Aliquots (10 microL) of Econail lacquer formulation containing 0.45 mg of [(14)C]-econazole with 18% 2-n-nonyl-1,3-dioxolane (test group) or without 2-n-nonyl-1,3-dioxolane (control group) were applied twice daily for 14 days to human nails that had been washed with ethanol before each morning's application. The hydration of the nail sample was well controlled to simulate normal physiological conditions. After 14 days of dosing, the inner ventral section of the nail plate was assayed for absorbed drug content, using a micrometer-controlled drilling and nail powder removal system. The mass balance values of [(14)C]-econazole in this study were 90.8 and 96.4% for the test and control groups, respectively. The weight-normalized econazole content in the ventral/intermediate nail plate center in the test group was 6-fold greater than that in the control (p = 0.008). The total econazole absorbed into the supporting bed cotton ball in the test group was nearly 200-fold greater than that in the control group (p = 0.008) over the 14-day period. The amount of econazole after dosing in the inner part of the human nail (potential diseased area) was 11.1 +/- 2.6 (SD) microg/mg of nail powder with 2-n-nonyl-1,3-dioxolane in the lacquer and 1.78 +/- 0.32 microg/mg without 2-n-nonyl-1,3-dioxolane (p = 0.008). The surface nail contained more econazole (p = 0.004), that is, nonabsorbed drug, where 2-n-nonyl-1,3-dioxolane was not part of the dosing solution. Econazole in the support bed under the nail (the total absorbed dose) was 47.5 +/- 22.0 mg in the lacquer with 2-n-nonyl-1,3-dioxolane and 0.2 +/- 0.1 mg in the lacquer without 2-n-nonyl-1,3-dioxolane (p = 0.008). Moreover the concentration in the deep nail layer in the test group is 14,000 times higher than minimum inhibitory concentration (MIC) believed necessary to inhibit the growth of infecting fungi (Dermatophytes species). In a subsequent study, [(14)C]-dioxolane did not penetrate the nail well. Therefore, the mechanism of enhancement of econazole penetration is at the formulation/nail interface.
Assuntos
Dioxolanos/farmacocinética , Econazol/farmacocinética , Unhas/metabolismo , Administração Tópica , Química Farmacêutica , Humanos , Permeabilidade/efeitos dos fármacosRESUMO
Macromolecules have gained interest as drug entities unto themselves and as transport facilitators to alter initial phases of percutaneous absorption. Two macromolecular polymers (MW 2081 and 2565) were designed to hold cosmetics and drugs to the skin surface by altering initial chemical and skin partitioning. The effect of these polymers on the partition coefficient (PC) of estradiol with powdered human stratum corneum (PHSC) and water was determined. There was no statistically significant effect on the PC when the concentration of estradiol was increased 100-fold (0.028-2.8 microg/mL), when the incubation time was increased from 0 to 24 h, or when PHSC was delipidized. The addition of a liphophilic polymer had no effect on the PC; however, the hydrophilic polymer showed a significant polymer concentration-dependent increase (p < 0.01) in log PC for estradiol concentrations. Thus, a macromolecular chemical has the potential to alter the partitioning of chemical into the outer layers of skin, the first step in percutaneous absorption.
Assuntos
Epiderme/efeitos dos fármacos , Estradiol/química , Polímeros/química , Água/química , Portadores de Fármacos , Epiderme/fisiologia , Estradiol/farmacologia , Humanos , Polímeros/farmacologia , PósRESUMO
Perchloroethylene (PCE) is a widely used volatile organic chemical. Exposures to PCE are primarily through inhalation and dermal contact. The dermal absorption of PCE from a soil matrix was compared in rats and humans using real-time MS/MS exhaled breath technology and physiologically based pharmacokinetic (PBPK) modeling. Studies with rats were performed to compare the effects of loading volume, concentration, and occlusion. In rats, the percutaneous permeability coefficient (K(P)) for PCE was 0.102 +/- 0.017, and was independent of loading volume, concentration, or occlusion. Exhaled breath concentrations peaked within 1 h in nonoccluded exposures, but were maintained over the 5 h exposure period when the system was occluded. Three human volunteers submerged a hand in a container of PCE-laden soil for 2 h and their exhaled breath was continually monitored during and for 2.5 h following exposure. The absorption and elimination kinetics of PCE were slower in these subjects than initially predicted based upon the PBPK model developed from rat dermal kinetic data. The resulting K(P) for humans was over 100-fold lower than for the rat utilizing a single, well-stirred dermal compartment. Therefore, two additional PBPK skin compartment models were evaluated: a parallel model to simulate follicular uptake and a layered model to portray a stratum corneum barrier. The parallel dual dermal compartment model was not capable of describing the exhaled breath kinetics, whereas the layered model substantially improved the fit of the model to the complex kinetics of dermal absorption through the hand. In real-world situations, percutaneous absorption of PCE is likely to be minimal.
Assuntos
Modelos Biológicos , Absorção Cutânea/efeitos dos fármacos , Poluentes do Solo/farmacocinética , Tetracloroetileno/farmacocinética , Administração Cutânea , Adulto , Idoso , Animais , Testes Respiratórios , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Endogâmicos F344 , Absorção Cutânea/fisiologia , Poluentes do Solo/administração & dosagem , Especificidade da Espécie , Tetracloroetileno/administração & dosagemRESUMO
The purpose of this study was to develop an assay method of the human inner nail plate and to compare nail drug penetration by a penetrating enhancing formulation (the test carrier formulation). The test carrier and saline formulations were tested using radiolabeled urea, ketoconazole, and salicylic acid. After twice dosing daily for 7 days on human nail plates, the under inner section of the nail plate was assayed for absorbed drug content using a unique drilling/removal system. Results show that the weight-normalized radioactivity contents of three chemicals in the inner intermediate nail plate center in the carrier formulation were two fold higher than those from saline (p < 0.05). Total radioactivity recovery of dosed [(14)C]-salicylic acid was 89 +/- 2% in the carrier formulation and 88 +/- 5% in saline. In saline formulation, salicylic acid showed greater binding to the outer nail, making it less bioavailable for the inner nail area. This didn't occur with carrier formulation. In conclusion, topical treatment of nail diseases such as onychomycosis is not yet sufficiently effective, likely because of minimal drug penetration into the inner nail plate where the disease perpetuates. The assay system has the unique characteristic of being able to assay the inner part of the nail where the disease resides.
Assuntos
Cultura em Câmaras de Difusão/instrumentação , Cultura em Câmaras de Difusão/métodos , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Unhas/química , Absorção/fisiologia , Radioisótopos de Carbono/análise , Química Farmacêutica , Portadores de Fármacos/administração & dosagem , Humanos , Unhas/metabolismoRESUMO
The contribution of benzene to body burden after skin absorption compared with that due to inhalation absorption is of potential interest in the setting and interpretation of benzene (inhalation) exposure standards. However, an understanding of the quantitative relationship between skin and inhalation absorption, under different exposure conditions, is required. Such knowledge may be gained through physiological based pharmacokinetic (PBPK) modeling. The intake of benzene to the body via inhalation has been studied extensively. Physiological parameters enabling the calculation of amounts of benzene entering the blood stream per unit time are readily available for use in a PBPK model. Unfortunately, some data (i.e., partition coefficients) that would enable biologically plausible calculation of amounts of benzene entering the blood stream via skin absorption in a PBPK model are not available. Hence, the aim of this research was to determine partition coefficients across the epidermal and dermal layers of human skin so that these could be used within a PBPK model to determine quantitatively the flow rate of benzene per unit time through intact skin into the blood stream. The partition coefficients found for blood substitute: viable epidermis and blood substitute: dermis were, respectively, 2.4 and 11.2. Partition coefficients for benzene : stratum corneum (4.2), whole skin : blood substitute (2.2), benzene : water (109/126), and benzene : blood substitute (55/59) also were determined for the purposes of validating the blood substitute: viable epidermis and blood substitute : dermis partition coefficients.