Ronald C. Wester

Regional variation in percutaneous absorption in man: measurement by the stripping method

SummaryThe influence of anatomic site on the relationship between total penetration of a molecule and its quantities present in the stratum corneum (SC) 30 min after application was quantified in an in vivo study. For each site, six male volunteers received two symmetrical applications of 1,000 nmol benzoic acid 14C to an area of 1 cm2 for 30 min. The first application permitted measurement of total absorption of benzoic acid within 4 days (urinary excretion method), while the second enabled determination of the quantity of benzoic acid in the SC at the end of the application time. Total penetration according to site is: back < arm < chest < thigh < abdomen < forehead, (with the forehead being three times more permeable than the back). Whatever the sites and the origin of the differences observed, the results show that the single measurement of the amounts of a compound present in the SC at 30 min postapplication appears sufficient to predict its total penetration, these two parameters being linearly correlated (r=0.97, P<0.001).

Percutaneous absorption in the rhesus monkey compared to man

Abstract A study was done to directly compare percutaneous absorption of selected compounds in the rhesus monkey and in man. Hydrocortisone, testosterone, and benzoic acid in the monkey showed the same low, middle, and high absorption as in man. Total percents absorbed were similar in the monkey and man. The rhesus monkey may be a suitable animal model for percutaneous absorption studies of relevance to man.

In vivo percutaneous absorption and decontamination of pesticides in humans

Regulators today face complex problems in assessing the health hazards associated with the use of pesticides. Pesticide exposure occurs at manufacturing, application, work area, and consumption situations, and in the air, water, and soil of our daily lives. The skin is the largest organ of the body and thus has become a major environmental port for pesticides to enter the body. In this paper, we review the principles of percutaneous absorption--the rate and extent that chemicals enter the body through the skin--using data currently available for pesticides.

In Vivo and in Vitro Percutaneous Absorption and Skin Decontamination of Arsenic from Water and Soil

The objective was to determine the percutaneous absorption of arsenic-73 as H3ASO4 from water and soil. Soil (Yolo County 65-California-57-8) was passed through 10-, 20-, and 48-mesh sieves. Soil retained by 80 mesh was mixed with radioactive arsenic-73 at a low (trace) level of 0.0004 microgram/cm2 (micrograms arsenic per square centimeter skin surface area) and a higher dose of 0.6 micrograms/cm2. Water solutions of arsenic-73 at a low (trace) level of 0.000024 micrograms/cm2 and a higher dose of 2.1 micrograms/cm2 were prepared for comparative analysis. In vivo in Rhesus monkey a total of 80.1 +/- 6.7% (SD) intravenous arsenic-73 dose was recovered in urine over 7 days; the majority of the dose was excreted in the first day. With topical administration for 24 hr, absorption of the low dose from water was 6.4 +/- 3.9% and 2.0 +/- 1.2% from the high dose. In vitro percutaneous absorption of the low dose from water with human skin resulted in 24-hr receptor fluid (phosphate-buffered saline) accumulation of 0.93 +/- 1.1% dose and skin concentration (after washing) of 0.98 +/- 0.96%. Combining receptor fluid accumulation and skin concentration gave a combined amount of 1.9%, a value less than that in vivo (6.4%) in the Rhesus monkey. From soil, receptor fluid accumulation was 0.43 +/- 0.54% and skin concentration was 0.33 +/- 0.25%. Combining receptor fluid plus skin concentrations gave an absorption value of 0.8%, an amount less than that with in vivo absorption (4.5%) in the Rhesus. These absorption values did not match current EPA default assumptions.(ABSTRACT TRUNCATED AT 250 WORDS)

Controlled release of benzoyl peroxide from a porous microsphere polymeric system can reduce topical irritancy

Skin absorption of benzoyl peroxide from a topical lotion containing freely dispersed drug was compared with that from the same lotion in which the drug was entrapped in a controlled-release styrene-divinylbenzene polymer system. In an in vitro diffusion system, statistically significant (p = 0.01) differences were found in the content of benzoyl peroxide in excised human skin and in percutaneous absorption. In vivo, significantly (p = 0.002) less benzoyl peroxide was absorbed through rhesus monkey skin from the polymeric system. This controlled release of benzoyl peroxide to skin can alter the dose relation that exists between efficacy and skin irritation. Corresponding studies showed reduced skin irritation in cumulative irritancy studies in rabbits and human beings, whereas in vivo human antimicrobial efficacy studies showed that application of the formulations containing entrapped benzoyl peroxide significantly reduced counts of Propionibacterium acnes (p less than 0.001) and aerobic bacteria (p less than 0.001) and the free fatty acid/triglyceride ratio in skin lipids. These findings support the hypothesis that, at least for this drug, controlled topical delivery can enhance safety without sacrificing efficacy.

In vitro percutaneous absorption of cadmium from water and soil into human skin

The objective was to determine percutaneous absorption of cadmium as the chloride salt from water and soil into and through human skin. Soil (Yolo County 65-California-57-8) was passed through 10-, 20-, and 48-mesh sieves. Soil retained by 80 mesh was mixed with radioactive cadmium-109 at 13 ppb. Water solutions of cadmium-109 at 116 ppb were prepared for comparative analysis. Human cadaver skin was dermatomed to 500-microns, and used in glass diffusion cells with human plasma as the receptor fluid (3 ml/hr flow rate) for a 16-hr skin application time. Cadmium in water (5 microliters/cm2) penetrated skin to concentrations of 8.8 +/- 0.6 and 12.7 +/- 11.7% of the applied dose from two human skin sources. Percentage doses absorbed into plasma were 0.5 +/- 0.2 and 0.6 +/- 0.6%, respectively. Cadmium from soil (0.04 g soil/cm2) penetrated skin at concentrations of 0.06 +/- 0.02 and 0.13 +/- 0.05% for the two human skin sources. Amounts absorbed into plasma were 0.01 +/- 0.01 and 0.07 +/- 0.03%. Most of the nonabsorbed cadmium was recovered in the soap and water skin surface wash. Binding of cadmium from water to soil was greater than binding from water to powdered human stratum corneum, supporting the lower absorption from soil than from water. Short-term exposure of cadmium in water to human skin for 30 min (bath or swim) resulted in skin uptake, which upon further perfusion (48 hr), absorbed into the plasma receptor fluid (systemic). Cadmium in soil was increased from 6.5 to 65 ppb.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo bioavailability and metabolism of topical diclofenac lotion in human volunteers

AbstractPurpose. The primary objective of this study was to determine the rate and extent of transdermal absorption for systemic delivery of diclofenac from Pennsaid (Dimethaid Research, Inc.) topical lotion into the systemic circulation after the lotion was applied to human volunteers, in an open treatment, non-blinded, non-vehicle controlled study. In addition, the in vivo metabolism of this topical diclofenac lotion has also been studied. Methods. Human volunteers were dosed with topical [14C]-diclofenac sodium 1.5% lotion on the knee for 24 h. Sequential time blood and urine samples were taken to determine pharmacokinetics, bioavailability and metabolism. Results. Topical absorption was 6.6% of applied dose. Peak plasma 14C occurred at 30 h after dosing, and peak urinary 14C excretion was at 24−48 h. The urinary 14C excretion pattern exhibits more elimination towards 24 h and beyond, as opposed to early urinary 14C excretion. This suggests a continuous delivery of [14C]-diclofenac sodium from the lotion into and through skin which only ceased when the dosing site was washed. Skin surface residue at 24 h was 26 ± 9.5% dose (remainder assumed lost to clothing and bedding). Extraction of metabolites from urine amounted to 7.4−22.7% in untreated urine, suggesting substantial diclofenac metabolism to more water soluble metabolites, probably conjugates, which could not be extracted by the method employed. Two Dimensional TLC analysis of untreated urine showed minimal or no diclofenac, again emphasizing the extensive in vivo metabolism of this drug. Treatment of the same urine samples with the enzymes sulfatase and (β-glucuronidase showed a substantial increase in the extractable material. Three spots were consistently present in each sample run, namely diclofenac, 3′hydroxy diclofenac and an intermediate polar metabolite (probably a hydroxylated metabolite). Therefore, there was significant sulfation and glucuronidation of both diclofenac and numerous hydroxy metabolites of diclofenac, but many of the metabolites/conjugates remain unidentified. Conclusions. There was a continuous delivery of diclofenac sodium from the lotion into and through the skin, which ceased after the dosing site was washed. The majority of the material excreted in the urine were conjugates of hydroxylated metabolites, and not the parent chemical, although further identification is required.

Human Cadaver Skin Viability for In Vitro Percutaneous Absorption: Storage and Detrimental Effects of Heat-Separation and Freezing

AbstractPurpose. For decades, human cadaver skin has been banked and utilized by hospitals for burn wounds and to study percutaneous absorption and transdermal delivery. Skin storage maintenance and confirmation of skin viability is important for both uses, especially for the absorption process where the in vivo situation is simulated. Methods. Our system uses dermatomed human cadaver skin immediately placed in Eagles MEM-BSS, and refrigerated after donor death, then transfered to the laboratory and placed in Eagles MEM-BSS with 50 μg/ml gentamicin at 4°C for storage. Results. Skin viability, determined by anaerobic metabolism where glucose is converted to lactose, was highest (p<0.000) during the 18 hours of the first day after donor death, decreased some 3-fold by day 2 (p<0.000), but then maintained steady-state viability through day 8. Viability then decreased by approximately one-half by day 13. Thus, using the above criteria, human skin will sustain viability for 8 days following donor death in this system. Heat-treated (60°C water for one minute) and heat-separated epidermis and dermis lose viability. Conclusions. Human skin viability can be maintained for absorption studies. It is recommended that this system be used, and that heat-separation and skin freezing not be used, in absorption studies where skin viability and metabolism might be contributing factors to the study.

In vivo percutaneous absorption of paraquat from hand, leg, and forearm of humans

This study determines the in vivo percutaneous absorption of paraquat in humans. Three skin sites of application were used in a crossover manner for six subjects. The percents of applied dose (9 micrograms/cm2) absorbed were 0.29 +/- 0.2 (SD) for the leg, 0.23 +/- 0.1 for the hand, and 0.29 +/- 0.1 for the forearm. This gives an in vivo absorption rate of 0.03 microgram/cm2 for the 24-h exposure. Paraquat can be absorbed in vivo through the skin of humans; however, it is considered a minimally absorbed chemical.

Racial differences in the in vivo percutaneous absorption of some organic compounds: a comparison between black, Caucasian and Asian subjects.

Individual differences exist between patients, and, for topical therapy, differences in skin due to race may be a consideration. Pharmacological response depends upon the percutaneous absorption and the inherent activity of the chemical once absorbed into the biological system. Our objective was to determine the in vivo percutaneous absorption of three test chemicals in human subjects with Asian (A), black (B) and Caucasian (C) ethnic skin. Following a 30 min topical application on the upper outer arm of 1 Μmol/cm214C-labeled chemical, percutaneous absorption was determined by both urinary excretion and the stripping technique. Amounts absorbed were: for benzoic acid 1.43 ± 0.27% (SD) (A), 1.07 ± 0.18% (B), 1.2 ± 0.19% (C); for caffeine 1.06 ± 0.17% (A), 1.01 ± 0.19% (B) and 0.96 ± 0.12% (C); for acetylsalicylic acid 1.8 ± 0.31% (A), 1.59 ± 0.31% (B) and 2.12 ± 0.36% (C). No statistical difference (P>0.05) was found in percutaneous absorption of benzoic acid, caffeine or acetylsalicylic acid between Asian, black and Caucasian subjects.