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Biomedical subjects

R C Wester

Publications and source records attributed to R C Wester.

88 records · Page 5Linked to original sources
PubMed1978

Effect of salicylic acid on the percutaneous absorption of hydrocortisone. In vivo studies in the rhesus monkey.

To document the effect of salicylic acid on hydrocortisone penetration in vivo in the rhesus monkey, hydrocortisone 14C, with and without salicylic acid, was applied in acetone and the solvent evaporated. The compounds also were applied in a formulation (60% ethanol, 5% propylene glycol, 5% glycerin, 30% water) in which salicylic acid enhances penetration in vitro. There was a difference in the kinetics of hydrocortisone absorption with the two formulations. In acetone, excretion of 14C peaked at 48 hours and then declined. With the other formulation, excretion peaked at 48 hours, maintained to 72 hours, and then declined. There was no statistical difference in the percutaneous absorption of hydrocortisone with the addition of salicylic acid. These in vivo data are in contrast to the reported enhancing effect of salicylic acid obtained with in vitro studies.

Animals↗
PubMed1977

Pharmacokinetics of beta-methyldigoxin in healthy humans II: Oral studies and bioavailability.

The pharmacokinetics of orally administered aqueous 3H-beta-methyldigoxin solutions were studied at two dose levels, 0.3 and 0.6 mg, in healthy human subjects. The drug and its metabolites were specifically assayed in biological fluids and compared with results after intravenous doses to the same subjects. No significant dose dependency was observed. The apparent half-life of absorption was 16+/-6 min (SEM). Digoxin was the only metabolite observed in the plasma and comprised 28.6+/-3.7% of the dose in the urine. 3H-beta-Methyldigoxin, renally excreted unchanged, comprised 25.7+/-1.7% (SEM). Water-soluble metabolites in the urine comprised 9.0+/-1.8%. Fecal and urinary excretion accounted for 85% of the dose at 144 hr. The oral absorption of unchanged 3H-beta-methyldigoxin from solution was 59+/-6% by area under the curve methods and 60+/-4% by renal excretion. A total of 73% of the dose in the solution was absorbed as beta-methyldigoxin and digoxin. First-pass metabolism prior to absorption was largely prehepatic and assignable to GI degradation; 21.9+/-2.8% was degraded with 12.8+/-4.0% to digoxin and 9.1+/-4.0% to water-soluble metabolites. From 14 to 18% of the administered oral dose did not reach the systemic circulation. Analog computer fitting of plasma and urine levels of drug and digoxin was consistent with the first-pass premise with a delayed absorption of GI-generated digoxin and other metabolites. There were no significant differences between the oral absorption of a tablet formulation and the solution. Orally administered beta-methyldigoxin solution delivered 97% cardioactivity as itself and digoxin with respect to an equivalent amount of intravenously administered digoxin. This value contrasts to the 140% delivered by intravenously administered beta-methyldigoxin on the premise of pharmacodynamic equivalence of systemically appearing digoxin and beta-methyl-digoxin. Literature reports on the oral bioavailability of solutions and solid dosage forms of digoxin were critically reviewed, but no reliable comparison of the extent and reproducibility of oral absorption of cardioactive agents from administered digoxin or beta-methyldigoxin could be made from the widely variable digoxin studies with nonspecific assays.

Administration, Oral↗
PubMed1977

Percutaneous absorption of testosterone in the newborn rhesus monkey: comparison to the adult.

Percutaneous absorption of testosterone was determined in newborn rhesus monkeys, an animal model which is relevant to man. Mean percentage of absorptions of 4 and 40 microng/cm2 in the newborn were, respectively, 22.5 +/- 2.2 (SD) and 6.8 +/- 2.1. Statistical comparisons (Student's t-test) of these results with those obtained with adults show no significant difference (P greater than 0.05) in skin penetration of testosternoe in newborn and adult rhesus monkeys. In the newborn, the efficiency of absorption (percentage) decreased when the topical dose was increased 10-fold. However, the total compound absorbed per cm2 area of skin actually increased from 0.9 to 2.7 microng. With one other newborn rhesus, a topical dose of 40 microng/cm2 was applied to the ventral forearm and the area was occluded for 24 hr. Percutaneous absorption was 14.7%, a value twice that from nonoccluded absorption. Systemic absorption from a topical dose becomes critical in the newborn because the ratio of surface area (cm2) to body weight (kilograms) in the newborn is 3 times that in the adult. Given equal application area of skin per newborn and adult, the systemic absorption in the newborn becomes 3 times that of the adult when based on kilograms body weight. With a different ratio of skin surfact to body weight, the therapeutic ratio probably is lower in the newborn than in the adult when the compound is applied topically.

Age Factors↗
PubMed1977

Frequency of application on percutaneous absorption of hydrocortisone.

This study determines the percutaneous absorption of hydrocortisone when applied as a single dose or on a repetitive basis. Application was to the shaved ventral forearm of the rhesus monkey, an animal model in which some relevance to man has been shown. Absorption was quantified by measuring 14C in aliquots of urine over five days. There was no substantial difference in total absorption when 13.3 microng/sq cm was applied as a single dose or when the 13.3 microng/sq cm was applied three times, totaling 40 microng/sq cm. However, when 40 microng/sq cm was applied as a single dose, absorption was substantially increased over 13.3 microng/sq cm applied either once or three times. Additionally, when the skin was washed between applications to remove previously applied material in the three application experiment, there was a statistically significant increase over not washing the skin. The clinical importance of these results to man will await appropriate clinical studies.

Administration, Topical↗
PubMed1976

Relationship of topical dose and percutaneous absorption in rhesus monkey and man.

[14C]Testosterone, [14C]hydrocortisone, and [14C]benzoic acid were applied to skin of the rhesus monkey and man, and percutaneous absorption was quantitated by measuring urinary excretion of 14C. In the rhesus, the concentration of testosterone was increased from 4 to 4000 mug/cm2 in 5 steps. The efficiency of absorption decreased from 18.4 +/- 9.5% to 1.4 +/- 0.8%. However, the total compound absorbed (per cm2 area) always increased, from a low of 0.7mug to 56 mug. In man, testosterone penetration was also dose dependent and very similar to that in rhesus. Increasing the dose of hydrocortisone 10-fold (4 to 40 mug/cm2) resulted in a decrease in efficiency of absorption in man (1.6 +/- 1.4% to 0.6 +/- 0.3%) and rhesus (2.9 +/- 0.8% to 2.1 +/- 0.6%). The total compound absorbed, however, increased manyfold in both species. As benzoic acid concentrations were increased in man from 3 to 2000 mug/cm2, the percent absorption decreased, from 37.0 +/- 16.3% to 14.4 +/- 3.8%. Benzoic acid absorbed increased from 1.1 mug to 288 mug (per cm2 area), representing almost a 300-fold increase in absorption. Values in the rhesus were similar.

Administration, Topical↗
PubMedDate not supplied

Diclofenac metabolic profile following in vitro percutaneous absorption through viable human skin.

The extent of metabolism of diclofenac sodium in excised viable human skin was investigated using combination HPLC and radioactivity assay. In an earlier diffusion experiment using an in vitro flow-through diffusion system, radiolabelled diclofenac sodium in either lotion (Pennsaid) or aqueous solution was applied to viable human skin, either as single dose or multiple dose (8 times over 2 days). In this study, the receptor fluid samples from the diffusion experiment were subjected to extraction and the aliquot was analysed using HPLC to separate diclofenac and authentic metabolites. Based on the radioactivity of each HPLC fraction, the collection time of the fractions was compared with the retention time of diclofenac and metabolites in standard solutions. The samples from a single or multiple dose application of lotion showed radioactivity in mainly one fraction, whose retention time corresponded with diclofenac. Other HPLC fractions showed none or only small amounts of radioactivity within the error range of the assay. The same results were obtained with the pooled samples from the application of the lotion or of aqueous solution. The results suggest that diclofenac sodium does not undergo metabolism in viable human epidermis during percutaneous absorption in vitro. Hence, with topical application to human skin in vivo, diclofenac will be delivered with minimal, if any, metabolism.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMedDate not supplied

Polychlorinated biphenyls (PCBs): dermal absorption, systemic elimination, and dermal wash efficiency.

The objectives of this study were to determine the dermal absorption, systemic elimination, and dermal wash efficiency for polychlorinated biphenyls (PCBs). 14C-Labeled 42% PCB and 14C-labeled 54% PCB were topically and parenterally administered to rhesus monkeys and guinea pigs. Dermal absorption, determined by 14C urinary excretion, was extensive. In guinea pigs, 33% of the applied 14C-labeled 42% PCB dose and 56% of the 14C-labeled 54% PCB dose were absorbed. In rhesus monkeys, 15-34% of the labeled 42% PCB was dermally absorbed, depending on the magnitude of the applied dose. 14C-labeled 42% PCB applied to guinea pig skin was immediately washed with water and acetone. Only 59% of the applied dose was removed from the skin. A post-24-h washing removed only 1% of applied labeled 42% PCB and 20% of applied labeled 54% PCB. Postcontamination washing cannot be assumed to remove all contaminated PCB from skin. The body elimination of 14C was continuous and slow, with elimination half-lives on the order of 2-3 d in the guinea pig and 4-7 d in the monkey. Only 50-65% of an intramuscular dose could be accounted for in urine and feces for up to 28 d excretion. The elimination half-lives following topical administration were not much greater than that following intramuscular administration. This suggests that PCBs are rapidly and extensively absorbed through the skin, and that they are then probably generally distributed throughout the body, and then slowly eliminated.

Animals↗
PubMedDate not supplied

Quantitative analysis of benzene by selected ion monitoring/gas chromatography/mass spectrometry.

A selected ion monitoring gas chromatographic/mass spectrometric method for the quantitative determination of benzene in air, breath, and blood was developed utilizing a headspace assay with benzene-d3 as an internal standard. Limits of detection for 2 ng/mL in blood and 0.1 ppb in a 5-L sample of air or breath were attained. The influence of contamination by background benzene on the analytical process was studied carefully. For cases where background contamination could not be adequately controlled, the assay was modified for the quantitative determination of labelled benzenes six mass units heavier than natural benzene (benzene-d6 or benzene-13C6). Use of the method for the analysis of natural benzene was illustrated for the measurement of background levels in urban smokers and nonsmokers.

Air↗
PubMedDate not supplied

A selected ion monitoring GC/MS assay for 3,4,4'-trichlorocarbanilide and its metabolites in biological fluids.

A selected ion monitoring gas chromatography/mass spectrometric method for the quantitative determination of 3,4,4'-trichlorocarbanilide (TCC) and its major metabolites (the 2'-hydroxy sulfate and the N- and N'-glucuronides) in human plasma and urine was developed using the deuterium-labelled compounds as internal standards. Limits of detection of 3 ng/mL in urine for the N-glucuronides and of 1.5 ng/mL in plasma for the 2'-hydroxy sulfate were attained. Use of the method was illustrated in a study in human subjects employing TCC-containing bar soaps.

Body Fluids↗
PubMedDate not supplied

Benzene percutaneous absorption: dermal exposure relative to other benzene sources.

Skin is one of several exposure routes whereby benzene, a widely distributed environmental contaminant that causes leukemia, enters the body, so accurate predictions of its percutaneous absorption are important for risk assessment. Determining benzene's skin-exposure dose and subsequent absorption is difficult because it has a low boiling point and exists as both liquid and vapor. Industrial and environmental benzene is present as a contaminant in other vehicles/solvents, and its percutaneous absorption is in part dependent upon co-solvent volatility. Co-solvents such as benzene in toluene rapidly evaporate from skin, whereas benzene contaminant in water is retained on skin longer due to water's lower volatility. Co-solvents can also affect benzene-skin partition coefficients; thus, permeability coefficients and percentage doses absorbed can vary many-fold. The exposure situation will determine percutaneous absorption, which, if low, can be overwhelmed by benzene intake from the food we eat and the air we breathe.

Air Pollutants↗
PubMedDate not supplied

Understanding percutaneous absorption for occupational health and safety.

Local and systemic toxicity from percutaneous absorption depends on a chemical's penetrating the skin, which is both a barrier to absorption and a primary route to the systemic circulation. The skin's barrier properties are such that fluids and precious chemicals are reasonably retained within the body, while foreign chemicals are restricted from entering the systemic circulation. The skin is a primary body contact with the environment and the route by which many chemicals enter the body. In most instances, the toxicity of the chemical is slight and/or its bioavailability is too low to cause an immediate response. However, some chemicals are toxic when applied to the skin, and more chemicals that come in contact with the skin are being found to be potentially toxic. This article describes percutaneous absorption, methods to determine it, and factors that can affect it.

Animals↗
PubMedDate not supplied

A real-time in-vivo method for studying the percutaneous absorption of volatile chemicals.

Realistic estimates of percutaneous absorption following exposures to solvents in the workplace, or through contaminated soil and water, are critical to understanding human health risks. A method was developed to determine dermal uptake of solvents under non-steady-state conditions using real-time breath analysis in rats, monkeys, and humans. The exhaled breath was analyzed using an ion-trap mass spectrometer, which can quantitate chemicals in the exhaled breath stream in the 1-5 ppb range. The resulting data were evaluated using physiologically-based pharmacokinetic (PBPK) models to estimate dermal permeability constants (Kp) under various exposure conditions. The effects of exposure matrix (soil versus water), occlusion versus non-occlusion, and species differences on the absorption of methyl chloroform, trichloroethylene, and benzene were compared. Exposure concentrations were analyzed before and at 0.5-hour intervals throughout the exposures. The percentage of each chemical absorbed and the corresponding Kp were estimated by optimization of the PBPK model to the medium concentration and the exhaled-breath data. The method was found to be sufficiently sensitive for animal and human dermal studies at low exposure concentrations over small body surface areas, for short periods, using non-steady-state exposure conditions.

Animals↗
PubMedDate not supplied

In vitro percutaneous absorption of [14C] ethylene glycol.

The objective of this study was to determine the percutaneous absorption of ethylene glycol through human skin in vitro. The in vitro diffusion cells were of the flow-through design with 1 cm2 surface area. Three separate donor skin samples, taken from the thighs of white males, 16, 37, and 57 years old, were used and three replicates were performed for each experiment. Phosphate buffered saline, at a flow rate of three ml per hour, served as the receptor fluid. The human cadaver skin samples were dermatomed to 500 microns. [14C]-labeled ethylene glycol was applied to the skin surface in acetone vehicle at a dose of 8 micrograms/cm2. After 24-hr dermal exposure, 18.28 +/- 11.66% of the applied dose was recovered in the receptor fluid, 8.29 +/- 5.02% in the skin and 12.53 +/- 6.77% in the skin surface wash (total accountability was 39.11 +/- 7.23%). Individual difference existed (P < 0.05) for the three human skin sources. The combined skin and receptor fluid partitioning resulted in a potential absorbed dose of 26.57% relative to the 8 micrograms/cm2 applied dose for a 24-hr exposure duration. This represents a flux of approximately 2 micrograms/cm2/24 hr or 0.09 micrograms/cm2/hr for ethylene glycol. The maximum flux observed was 2.82%/hr/cm2 or 0.25 micrograms/cm2/hr.

Adolescent↗