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Biomedical subjects

R L Bronaugh

Publications and source records attributed to R L Bronaugh.

At least 19 recordsLinked to original sources
PubMed1992

In vitro release of nitroglycerin from topical products by use of artificial membranes.

An in vitro testing method for measuring the release of nitroglycerin from topical drug products was evaluated. The method involved measuring the amount of nitroglycerin that diffused from ointments and patches through various synthetic membranes into receptor fluid contained in a modified Franz diffusion cell. Plots of the amount of nitroglycerin released against the square root of time for all 10 synthetic membranes were linear. Five membranes (group I) were found to release nitroglycerin at similar rates (difference not significant; p > 0.05). Use of the other five membranes (group II) in diffusion cells resulted in release rates significantly slower than those of group I membranes (p < 0.05). Rapid permeation of nitroglycerin from a solution through a polysulfone membrane demonstrated a lack of significant diffusion barrier properties of this membrane. Rates of release of nitroglycerin from commercially available ointments were found to be similar. A comparison of three commercial nitroglycerin patches revealed that these products released nitroglycerin at different rates in vitro.

Administration, Cutaneous↗
PubMed1992

Percutaneous absorption and metabolism of pyrene, benzo[a]pyrene, and di(2-ethylhexyl) phthalate: comparison of in vitro and in vivo results in the hairless guinea pig.

The in vitro and in vivo absorption and metabolism of pyrene, benzo[a]pyrene, and di(2-ethylhexyl) phthalate (DEHP) were investigated in the hairless guinea pig. The in vitro method, which involved the use of flow-through diffusion cells and Hepes-buffered Hanks' balanced salt solution containing 4% bovine serum albumin as perfusate, was demonstrated to be a suitable system for predicting in vivo absorption of the above lipophilic compounds. The successful application of the in vitro technique for these compounds is significant because no satisfactory in vitro method has hitherto been developed to predict in vivo absorption of highly lipophilic chemicals. Quantification of parent compounds and metabolites that permeated into perfusates and those that remained in skin discs provided insight into the process by which the chemicals penetrated through the skin. Pyrene was absorbed primarily by a passive diffusion process, although a small fraction of the administered dose was biotransformed into metabolites in the skin and partitioned into the receptor fluid. Absorption of benzo[a]pyrene was mediated by biotransformation processes. A metabolite derived from the ultimate carcinogen of this compound, benzo[a]pyrene r-7, t-8,9,10-tetrahydrotetrol, was identified in the receptor fluid. Most of the administered DEHP remained in the skin and only a very small fraction of the dose partitioned into the receptor fluid in either viable or nonviable skin. Data from the present study led to the conclusion that the in vitro method can be utilized to predict in vivo absorption for compounds of high lipophilicity and that dermal metabolism facilitates partitioning of metabolites into the receptor fluid and hence may affect the biological activities of dermally applied compounds.

Administration, Cutaneous↗
PubMed1991

Percutaneous absorption/metabolism of phenanthrene in the hairless guinea pig: comparison of in vitro and in vivo results.

The in vitro and in vivo percutaneous absorption/metabolism of phenanthrene was investigated in hairless guinea pigs. Flow-through diffusion cells and Hepes-buffered Hanks' balanced salt solution (HHBSS) as receptor fluid were used in the in vitro system. When phenanthrene was applied to excised guinea pig skin mounted on the cells at dose levels of 6.6 and 15.2 micrograms/cm2, 89.7 and 79.1% of the administered doses were respectively absorbed into the skin and receptor fluids during a 24-hr perfusion period. These results are consistent with the in vivo data which showed approximately 80% absorption over the same period of time. Phenanthrene was metabolized in vitro into phenanthrene 9,10-dihydrodiol, 3,4-dihydrodiol, 1,2-dihydrodiol, and traces of hydroxy phenanthrenes. Of the materials absorbed in vitro, 92% was the parent compound and 7% the dihydrodiol metabolites. When a nonviable in vitro system was used, 68% of the applied 15.2 micrograms/cm2 dose was absorbed. Data from the present study demonstrate that the in vitro system is a good model for predicting in vivo percutaneous absorption of phenanthrene, and that penetration of phenanthrene through the skin is controlled more by the passive rate of diffusion than by metabolism.

Animals↗
PubMed1990

Metabolism of xenobiotics during percutaneous penetration: role of absorption rate and cutaneous enzyme activity.

The role of absorption rate and enzyme activity on cutaneous metabolism of topically applied xenobiotics was assessed by determining the simultaneous percutaneous penetration/metabolism of benzo[a]pyrene (B[a]P) and 7-ethoxycoumarin (7-EC) in intact, metabolically viable skin of Sencar mice, hairless guinea pigs, and humans. In addition, specific activities of aryl hydrocarbon hydroxylase (AHH) and ethoxycoumarin deethylase (ECDE) were determined in cutaneous microsomal fractions. Both compounds were readily absorbed but only minimally metabolized. Sencar mouse and hairless guinea pig skin absorbed 55-60% of the applied B[a]P dose and metabolized only 6 and 3%, respectively, of that absorbed. Human skin absorbed 31% of the applied dose and B[a]P metabolism was not detectable. All three species absorbed 60-80% of the applied 7-EC dose. Sencar mouse and hairless guinea pig skin metabolized 1.3 and 1.2% of the absorbed dose, respectively. and human skin metabolized only 0.05%. When 7-EC absorption was increased to the maximum possible rate, its metabolism by Sencar mouse and hairless guinea pig skin was also substantially increased. In human skin, a much smaller increase in 7-EC absorption rate was possible and no increase in 7-EC metabolism occurred. Thus relatively slower absorption of 7-EC and B[a]P by human skin may limit cutaneous metabolism of these penetrating compounds. Specific activities of AHH and ECDE were significantly lower in human skin than in Sencar mouse and hairless guinea pig skin, suggesting that low enzyme activity contributes as well to a low rate of metabolism by human skin compared to other species. Thus absorption rate and cutaneous enzyme activity are interrelated determinants of the extent of cutaneous metabolism of B[a]P and 7-EC occurring during their percutaneous penetration, and slow absorption and low enzyme activity limit cutaneous metabolism of B[a]P and 7-EC in human skin in particular.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1990

In vivo percutaneous absorption of fragrance ingredients in rhesus monkeys and humans.

The percutaneous absorption of the fragrance diethyl maleate was measured in vivo in human and monkey studies. With the application sites occluded, 54% of the applied dose of the volatile fragrance penetrated human skin in 24 hr compared with 69% absorption in the monkey skin. It was concluded that the monkey is a good model for human skin with regard to the penetration of this fragrance material since no significant difference in the absorption of diethyl maleate was observed. The percutaneous absorption of the fragrances benzyl acetate and five other benzyl derivatives (benzyl alcohol, benzyl benzoate, benzamide, benzoin and benzophenone) was determined in vivo in monkeys. Absorption through occluded skin was high for all compounds (approximately 70% of the applied dose in 24 hr) and no significant differences between the values for the different compounds were observed. No correlations were seen between skin penetration of these compounds and their octanol-water partition coefficients. Under unoccluded conditions skin penetration of the fragrances was reduced and there was great variability between compounds, presumably because of variations in the rates of evaporation from the site of application. The data suggest that humans may have significant systemic exposure to these fragrance materials.

Administration, Topical↗
PubMed1990

In vitro skin absorption and metabolism of benzoic acid, p-aminobenzoic acid, and benzocaine in the hairless guinea pig.

The percutaneous absorption and metabolism of three structurally related compounds, benzoic acid, p-aminobenzoic acid (PABA), and ethyl aminobenzoate (benzocaine), were determined in vitro through hairless guinea pig skin. Benzocaine was also studied in human skin. Absorption of benzocaine was rapid and similar through both viable and nonviable skin. The absorption of the two acidic compounds, benzoic acid and PABA, was greater through nonviable skin. A small portion (6.9%) of absorbed benzoic acid was conjugated with glycine to form hippuric acid. Although N-acetyl-benzocaine had not been observed as a metabolite of benzocaine when studied by other routes of administration, both PABA and benzocaine were extensively N-acetylated during percutaneous absorption. Thus, the metabolism of these compounds should be considered in an accurate assessment of absorption after topical application.

4-Aminobenzoic Acid↗
PubMed1989

Maintenance of skin viability during in vitro percutaneous absorption/metabolism studies.

The assessment of cutaneous metabolism during in vitro percutaneous absorption studies requires maintenance of the viability of the skin section. With the use of flowthrough diffusion cells, Eagle's minimal essential medium (MEM), Hepes-buffered Hanks' balanced salt solution (HHBSS), or Dulbecco modified phosphate-buffered saline (DMPBS), acting as receptor fluids, were able to sustain aerobic and anaerobic glucose utilization, testosterone and estradiol metabolism, and histopathological appearance of perfused rat skin sections for 24 hr. Fetal bovine serum supplements were not required for survival and appeared to inhibit the extraction of the metabolite estrone from the receptor fluid fractions in estradiol absorption/metabolism experiments. The use of phosphate-buffered saline (PBS) resulted in elimination of aerobic and anaerobic glucose utilization in 12 hr and declining appearance of steroid metabolites in receptor fluid fractions during the 24-hr percutaneous absorption/metabolism studies. Histopathological examination of skin sections perfused with PBS for 24 hr showed autolysis of the viable epidermis and dermis. The results demonstrate that an appropriate receptor fluid, such as MEM, HHBSS, or DMPBS, is required for percutaneous absorption studies in which cutaneous metabolism of the penetrating compound is to be considered.

Analysis of Variance↗
PubMed1989

Extent of cutaneous metabolism during percutaneous absorption of xenobiotics.

In vitro percutaneous absorption studies generally do not determine whether biotransformation occurs during passage of a substance through the skin. Since it has recently been demonstrated that several chemicals are metabolized during skin permeation, we investigated the metabolism of five additional compounds (14C-labeled) after application to fuzzy rat skin: caffeine, p,p'-DDT, butylated hydroxytoluene (BHT), salicylic acid, and acetyl ethyl tetramethyltetralin (AETT). The viability of skin was maintained with a tissue culture medium. Radioactivity of each substrate and any metabolites in skin and receptor fluid was measured so that the absorption and metabolism of water-insoluble compounds would be accurately determined. Percutaneous absorption ranged from a low of 13% of the applied dose for BHT to a high of 49% for DDT. BHT was metabolized in skin to 4-hydroxy-BHT and an unknown metabolite. Of the absorbed radioisotope, 6.6% was isolated in biotransformed products found mainly in the receptor fluid. AETT was also metabolized during absorption, with 1.9% of the absorbed radioisotope found in two unknown peaks. Caffeine, DDT, and salicylic acid were not metabolized during skin permeation. Skin and liver microsomal metabolism was measured for all compounds except DDT. Metabolism in skin was observed only for the compounds also biotransformed in the diffusion cell; BHT and AETT were metabolized at 113 and 2.5 pmol/min/mg protein, respectively. In this study, as in others, skin metabolism was substantially less than the corresponding metabolism in liver. Therefore, a low rate of liver metabolism such as that found for caffeine, salicylic acid, and DDT might often be predictive of the absence of measurable metabolism during skin permeation. It seems likely that for many compounds, the biotransformations in skin will be small in terms of the percentage of absorbed material that is metabolized. Nevertheless, with potent compounds, even small quantities of a metabolite can be important and for pharmacokinetic studies, viability of skin must be maintained.

Animals↗
PubMed1986

Methods for in vitro percutaneous absorption studies. VI: Preparation of the barrier layer.

The skin membrane for in vitro percutaneous absorption studies was prepared so that it was similar in thickness to the in vivo barrier layer. A dermatome section from the skin surface produced a layer of skin that included the epidermis and papillary dermis (location of capillary loops) but without most of the dermal tissue. Improved absorption measurements were then obtained with hydrophobic compounds with the use of a polyethylene glycol 20 oleyl ether (PEG-20 oleyl ether) receptor fluid. With the haired rat, preparing a skin section 300-micron thick (and pretesting for damage to the barrier with H3-water) resulted in a membrane that gave values in good agreement with in vivo results for 3-phenyl-2-propenyl 2-aminobenzoate (cinnamyl anthranilate) (1) and benzo(a)pyrene absorption. When sparsely haired fuzzy rat skin was used, a section of skin 200-micron thick could be prepared without the need for pretesting for damage. Good agreement was obtained between in vivo and in vitro values for 1-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)etha none (acetyl ethyl tetramethyl tetralin) (2) and DDT with 0.5% PEG-20 oleyl ether in water as the receptor fluid. The skin of the fuzzy rat seemed more similar in permeability to human skin than did the skin of the hairless mouse when the absorption of six compounds was compared.

Animals↗
PubMed1986

Methods for in vitro percutaneous absorption studies. VII: Use of excised human skin.

Water permeability constants (Kp) were determined with skin from human cadavers. No difference was seen in Kp values from unfrozen skin or from skin frozen for a few days. Human skin could usually be stored at -20 degrees C for up to a year with no change in water permeability, but in some cases apparent deterioration of the barrier was observed. A rapid procedure was developed for checking barrier integrity of skin in diffusion cells before a penetration study. The percent of the water dose absorbed after 20-min contact with skin correlated with water Kp values. Changes in water permeation through human skin agreed with changes in the absorption of seven test compounds of varying solubility properties (acetylsalicylic acid, benzo(a)pyrene, cortisone, DDT, nicotinic acid, propylene glycol, and testosterone). Water permeation is therefore considered to be a good indicator of potential changes in the barrier integrity of human skin. No correlation was observed in Kp values and other characteristics of the donor skin samples such as age, sex, race, and length of time before skin harvest.

Body Water↗
PubMed1986

Differential rates of percutaneous absorption through the eczematous and normal skin of a monkey.

A monkey (Macaca fascicularis), diagnosed as having eczematous dermatitis on the basis of histopathology of a skin biopsy, was used to study the percutaneous absorption of 2 anti-inflammatory steroids. Absorption was measured through involved and uninvolved skin by using in vitro diffusion cell techniques. Hydrocortisone (0.5%) and triamcinolone acetonide (0.1%) were applied to the skin in a petrolatum vehicle. After application for 24 h, the permeation of hydrocortisone was approximately doubled (from 2.6 to 5.5% of the applied dose) when diseased skin was used. The absorption of triamcinolone acetonide was enhanced through the eczematous skin during the initial 12 h. At 24 h, however, no significant difference in total absorption was obtained.

Absorption↗
PubMed1986

Vehicle effects on percutaneous absorption: in vivo and in vitro comparisons with human skin.

The percutaneous absorption of benzoic acid, caffeine and testosterone through human skin was measured by using in vivo and in vitro techniques. The compounds were applied to the skin in solution in three vehicles: petrolatum, ethylene glycol gel and water gel. Because benzoic acid was ionized at the neutral pH of the gels, these data were difficult to interpret and are not reported. The stratum corneum/vehicle partition coefficients (Km) and percent saturation of the vehicles with substrate were determined to aid in the interpretation of the absorption results. In the in vitro studies, the permeability constants determined for the compounds in each vehicle correlated with either the Km value or the percent saturation of the vehicle. Caffeine penetrated most readily from a petrolatum vehicle, and the greatest testosterone absorption was from a water gel. Permeation was also expressed in terms of the percentage of the applied dose absorbed. Reasonable agreement was obtained between the in vivo and in vitro values. Although no significant differences occurred between most values compared, there was a trend toward lower penetration in the in vitro system.

Adult↗
PubMed1985

Methods for in vitro percutaneous absorption studies IV: The flow-through diffusion cell.

A flow-through diffusion cell system for percutaneous absorption studies has been developed. The results of initial studies with a limited number of compounds are reported. The cells were constructed from Teflon and contained a glass window in the bottom for viewing the receptor contents. A flow rate of at least 5 mL/h is required through the receptor (volume, 0.4 mL) for accurate results. The skin permeation of water, cortisone, and benzoic acid was determined in the flow-through cell and a standard static-diffusion cell. The absorption profiles and quantitative values obtained were similar for the two types of cells. The permeation of cortisone and benzoic acid applied in a petrolatum vehicle was determined in vivo in rats and with rat skin in the flow-through and static-diffusion cells. Good agreement was obtained between the results of the in vivo and in vitro procedures. The percutaneous absorption of a hydrophobic compound [3-phenyl-2-propenyl 2-aminobenzoate (cinnamyl anthranilate)] was enhanced with normal saline receptor solution in the flow-through cell when compared with results in the static cell. Maximum in vitro absorption was obtained with either cell using a 6% solution in water of the nonionic surfactant polyethylene glycol 20 oleyl ether (PEG-20 oleyl ether).

Animals↗
PubMed1985

Methods for in vitro percutaneous absorption studies V: Permeation through damaged skin.

The permeation of compounds through skin damaged by different methods was compared because agents that are absorbed through skin are sometimes applied to a damaged barrier. The removal of the stratum corneum by stripping the skin with cellophane tape was the most effective method for enhancing absorption. A minimal increase in water permeation was obtained when one abrasion line was made with a hypodermic needle, but the absorption increased substantially when three to six lines were made across the site of application. Similar values were obtained with in vivo and in vitro techniques for penetration of cortisone and nicotinic acid through normal and abraded rat skin. Sever damage by UV irradiation to rats in vivo resulted in nicotinic acid absorption similar to that obtained in vitro through abraded or tape-stripped skin. Damage from mild irradiation could not be accurately duplicated by in vitro methods. The magnitude of the increase in absorption of seven chemicals through abraded human and rat skin was related to the extent to which the molecules were absorbed by the skin. The greatest increases in penetration were obtained with the compounds that were most poorly absorbed.

Animals↗
PubMed1985

Comparison of percutaneous absorption of fragrances by humans and monkeys.

The percutaneous absorption of two cosmetic fragrance materials, safrole and cinnamyl anthranilate, as well as of cinnamic alcohol and cinnamic acid, has been measured at occluded and non-occluded application sites. Absorption values were determined in the rhesus monkey in vivo. Absorption through human skin was measured by using excised skin in diffusion cells. Because of the insolubility in water of safrole and cinnamyl anthranilate, a nonionic surfactant solution (6% oleth 20) was used in the receptor chamber of the diffusion cell in order to facilitate the partitioning of the compounds from the skin into the receptor fluid. The relative volatility of the compounds was determined in order to aid in the interpretation of the absorption results. The greatest difference between in vivo and in vitro absorption values occurred with safrole, which was the least well absorbed and the most volatile compound. Cinnamic acid absorption through non-occluded human skin (17.8 +/- 4.9%, mean +/- SEM) was significantly lower than through monkey skin (38.6 +/- 8.3%). The values for absorption through human and monkey skin did not differ significantly for cinnamyl anthranilate (24.0 +/- 5.1% v. 26.1 +/- 2.3%) or cinnamic alcohol (33.9 +/- 7.3% v. 25.4 +/- 4.4%). Occlusion of the skin resulted in greater permeation of all of the compounds; a significant difference in permeability between the two types of skin occurred only with safrole. The fragrances were absorbed well, but their volatility must be considered in a toxicity evaluation. There was reasonable agreement between the values obtained from the studies of the human skin in vitro and the monkey skin in vivo.

Animals↗
PubMed1985

Percutaneous absorption of nitroaromatic compounds: in vivo and in vitro studies in the human and monkey.

The percutaneous absorption of 2-nitro-p-phenylene-diamine, 4-amino-2-nitrophenol, nitrobenzene, p-nitroaniline, and 2,4-dinitrochlorobenzene was measured through human and monkey skin. Human studies were performed with excised skin in diffusion cells. Absorption through monkey skin was measured by in vivo and in vitro techniques. Results were compared with those from previously reported human in vivo studies on 2,4-dinitrochlorobenzene and nitrobenzene. Rapid penetration was observed with all compounds, with maximum absorption occurring the first few hours. No significant differences in absorption were found in values obtained by the different procedures except for the highly volatile (and therefore difficult to compare) compound nitrobenzene. A comparison of the human and monkey in vitro data showed a trend toward increased absorption through monkey skin, but the increase was not statistically significant. The monkey in vivo and in vitro results showed that absorption of all compounds except nitrobenzene was slightly less in the in vitro studies; however, the values were not significantly different. The relative volatility of these nitroaromatic compounds was measured by the loss of compound from epidermal discs at various time intervals. The greatest loss of applied material occurred with nitrobenzene; however, substantial amounts of the other compounds were lost, particularly during the first minute after application as the acetone vehicle evaporated. Monkey skin was found to be a good model for human skin for the determination of the percutaneous absorption of these compounds, and in vitro measurements of absorption agreed reasonably well with values obtained by in vivo techniques. A good correlation was not observed between the absorption of these compounds and their solubility properties.

Aniline Compounds↗
PubMed1978

The evaluation of topical anti-inflammatory activity on rat ears subjected to thermal injury.

Topical anti-inflammatory activity of steroidal and non-steroidal agents was assessed on inflammation produced by heat. A burn was produced on the ears of rats and the inflammation was quantitated gravimetrically. Steroidal anti-inflammatory agents were ranked in order of decreasing activity: triamcinolone acetonide, dexamethasone, prednisolone and hydrocortisone acetate. The nonsteroidal agents phenylbutazone and indomethacin were also effective in inhibiting the inflammation. Cholesterol, a steroid devoid of anti-inflammatory activity, was inactive in this test. Hydrocortisone acetate, in particular, appears to be less effective in inhibiting this type of inflammation than inflammation produced by croton oil.

Administration, Topical↗