Percutaneous Absorption Rate Research Articles

In vivo percutaneous absorption studies of volatile organic solvents in hairless mice II. Toluene, ethylbenzene and aniline

Percutaneous absorption studies were conducted with three single-ring, radiolabeled aromatic solvents (benzene derivatives) using a recently described direct method for studying volatile chemicals in hairless mice. Total absorption, determined from the sums of radioactivity found in the excreta, expired breath and carcass, was 2.1+, 3.4% and 4.7% of the nominal dose for toluene, ethylbenzene and aniline, respectively. Breath decay curves indicated that absorption of toluene and ethylbenzene was complete by 15 min after application and that by this time the excretion rate of aniline exceeded the absorption rate. Evaporation rates were used to derive estimated contact times, and these in turn were used in conjunction with the absorbed doses to estimate percutaneous absorption rates. Equivalent dermal exposures (cm2.min) that would yield body burdens equivalent to those expected following 8-h inhalations at existing US permissible exposure limits during light work were calculated. The data indicate that dermal absorption of these compounds could approach or exceed that from inhalation under some work conditions. Correlations between absorption and various physical properties were evaluated using Spearman's correlation coefficients. The physical properties evaluated included volatility, solubility, octanol/water partition coefficients and melting points. For this limited series of benzene derivatives, two measures of volatility, i.e. vapor pressure and boiling point, were the only physical properties significantly correlated with percutaneous absorption.

Enhancing effect of cetyl lactate on the percutaneous absorption of indomethacin in rats.

The enhancing effect of cetyl lactate (CL) on the percutaneous absorption of indomethacin (ID) from test solutions in propylene glycol (PG) was investigated by using the abdominal skin of rats in vivo. The percutaneous absorption rate of ID from 1 or 3% CL-PG test solution through the intact skin of rats was observed to be faster than that from the control solution (without CL). The bioavailability of ID was about 0.04% for the control solution, 2.2% for 1% CL-PG and 6.8% for 3% CL-PG test solutions. These results suggest that CL functions as an enhancer for the percutaneous absorption of ID. Furthermore, marked enhancing effects on percutaneous absorption of ID were obtained at a concentration greater than 1% CL in PG. In order to elucidate the mode of action of CL as an absorption enhancer, the percutaneous absorption of ID from the control solution and 3% CL-PG test solution through damaged skin from which the stratum corneum had been stripped was additionally investigated. It was confirmed that CL acts on the stratum corneum to produce its effect.

Effect of several enhancers on the skin permeation of water-soluble drugs.

Since the percutaneous absorption rates of water-soluble drugs are low in general, an enhancing system is needed when using the skin as an administration site for the drugs. We have investigated the effect of various penetration enhancers on the in vitro and in vivo percutaneous absorptions of catecholamine analogs, i.e. levodopa (LD), dopamine hydrochloride (DPH) and isoproterenol hydrochloride (IPH), as model water-soluble drugs. It was found that medium-chain glycerides (Sefsol 318) markedly enhanced the in vitro permeation of the drugs through excised hairless rat skin among the enhancers tested in the present experiments; the permeation rates with 5% Sefsol 318 in water were about 65, 34 and 53 times higher than the corresponding control (without enhancer) for LD, DPH and IPH, respectively. In addition, the in vivo percutaneous absorption experiments showed that the blood levels of these drugs after application of aqueous gels containing 5% Sefsol 318 on rat skin were higher than those in the absence of enhancer. Drug levels in the liver and kidney were also higher than without Sefsol 318. Percutaneous administration of DPH with Sefsol 318 to hairless rats resulted in lower diastolic blood pressure and a slightly higher heart rate with as compared to administration without the enhancer. These results suggest that Sefsol 318 is a potential candidate to enhance the transdermal absorption of water-soluble drugs.

Studies on computer optimization techniques for hydrophilic vehicle compositions

The influence of hydrophilic vehicles on percutaneous absorption rate of griseofulvin was studied using intact skin of full thickness of hairless rat. Thein vitro absorption rates were used as the characteristics for deciding the optimum formula of ointment vehicles. The optimum formula of vehicle compositions for maximum absorption rate was obtained from the polynomial regression equation and the two graphical techniques, contour graph and partial derivative graph. It was composed of sodium lauryl sulfate (1.65 W/W%), white petrolatum (16.5 W/W%), propylene glycol (12.0 W/W%), and stearyl alcohol (19.6 W/W%). The experimental value obtained from the optimum formula and the prediction value were 33.99 and 33.87 μg/√min, respectively. From these results, it was believed that optimum formula for semisolid dosage forms could be obtained from the application of the optimization technique used in this study.

The Relationship between the Rate of Percutaneous Absorption and the Biological Activity of Testosterone and Various Esterified Analogues

The Relationship between the Rate of Percutaneous Absorption and the Biological Activity of Testosterone and Various Esterified Analogues

Percutaneous uptake rate of 2-butoxyethanol in the guinea pig.

The percutaneous absorption rate and elimination kinetics of 2-butoxyethanol (ethylene glycol monobutyl ether) were estimated in the guinea pig. An intravenous bolus dose of 42 or 92 mumol/kg of body weight was administered into the jugular vein of 10 pentobarbital-anesthetized animals. Epicutaneous administration of 2-butoxyethanol followed 2.5 h later in one or two sealed glass rings on the clipped back of the animal. Arterial blood samples were obtained and then analyzed for 2-butoxyethanol by gas chromatography. Following the intravenous dose, the apparent total clearance and mean residence time of 2-butoxyethanol were calculated to be 128 ml X min-1 X kg-1 (SD 30%) and 4.7 min (SD 30%), respectively. During the latter part of the 2-h skin exposure, the concentration of 2-butoxyethanol in the blood appeared to level off at an average concentration of 21 mumol/l (SD 45%). The absorption rate through the skin was estimated to be 0.25 (range 0.05-0.46) mumol X min-1 X cm-2 (SD 49%). The skin uptake rate in the guinea pig was extrapolated to man for a comparison of the percutaneous absorption of liquid solvent with respiratory uptake of solvent vapor. The extrapolation indicated a risk of acute adverse effects when large areas of the skin are exposed to 2-butoxyethanol.

A method of predicting percutaneous absorption rates from vehicle to vehicle: an experimental assessment

The solubility of water in a range of polar solvents was determined. The absorption rate of tritiated water from half-saturated solutions of water in each of the solvents (vehicles) was measured through human abdominal epidermis in vitro and results were expressed as permeability constants. In agreement with theory, the tritiated water permeability constant was inversely proportional to the mole fraction solubility of water in the vehicles. This change in permeability constant with the reciprocal of solubility was found to be attributable to changes in the stratum corneum: vehicle partition coefficient whilst no distinct solubility-related variations in the calculated stratum corneum diffusion constant were apparent. These results are in accord with skin permeability and thermodynamic theory which, for a particular penetrant, indicate that the absorption rate will be proportional to the thermodynamic activity of the penetrant in the vehicle if the properties of the stratum corneum are not changed by the vehicles. The comparison of penetrant solubilities provides one means of relating the thermodynamic activity in one vehicle to that in another. Thus measurement of the percutaneous absorption rate (or a related parameter) for a penetrant in one, or preferably several, vehicles may permit calculations of absorption rates from other vehicles based on solubility data. The relationships employed in the calculations are: absorption rate equals permeability constant multiplied by the applied concentration; permeability constants are inversely proportional to the mole fraction solubilities of the penetrant in the vehicles. This predictive treatment should be equally successful whether based on in vitro or in vitro measurements of absorption rates.

Percutaneous absorption of chemical substances and toxicity. Especially about organic solvents.

A critical factor in the evaluation of the risk associated with cutaneous exposure to chemical substances is an information relating to the percutaneous absorption of these substances. Recent developments in the percutaneous absorption of chemical substances in industry, especially organic solvents, are reviewed, and these percutaneous absorption rates in humans and animals exposed in vivo and their excised skin in vitro from vapor and liquid phase are summarized. Evaluations concerning the amounts of percutaneous absorption in vivo of organic solvents in toxicity are discussed by a mathematical model by using the percutaneous absorption coefficient for vapor phase and the percutaneous absorption rate for liquid phase, and recommendations for future research of organic solvents are proposed from the relationship between these chemical-physical properties and these percutaneous absorption rates.

Percutaneous Absorption: A New Physicochemical Predictive Model for Maximum Human In vivo Penetration Rates

A diffusion model for stratum corneum-limited percutaneous absorption based on the interaction of the diffusate with the stratum corneum was derived. Two types of interactions were proposed, ion-dipole and lipidlipid, based on current knowledge of the stratum corneum and on irreversible thermodynamic arguments. The resulting flux equations predict a linear dependence of flux on the dipole moment and In X of the diffusates, where X is the mole fraction solubility. These flux equations were tested on 21 different diffusates whose human percutaneous absorption rates in vivo had been previously determined. A solubility method was used to classify the interaction pathway for each diffusate. Correlation of the maximum absorption rate for the lipid and polar pathways give correlation coefficients of 0.946 and 0.998, respectively. It is believed that these studies provide a starting point for the ultimate goal of percutaneous absorption research: to be able to bypass in vivo and in vitro studies and to predict absorption solely on the basis of the physicochemical properties of the diffusates.

Percutaneous Penetration of Three Insecticides in Rats: A Comparison of Two Methods for In Vivo Determination

Percutaneous penetration of three insecticides was studied by two methods. The indirect (excretion analysis) and direct (skin patch removal) methods for determining penetration were compared in rats. Radiolabeled solutions of parathion, carbaryl, and DDT were applied to previously shaved rats at the rate of 4 micrograms/cm2. Recoveries of radioactivity in urine, feces, application site, and various tissues were measured at intervals over a 5-day period. Urinary excretion rates were corrected for incomplete excretion by intraperitoneal applications. In the 5 days following intraperitoneal administration, the urinary excretion of parathion and carbaryl was greater than 80% while less than 5% of DDT was excreted. A good correlation was found between the indirect and direct methods utilized to determine percutaneous absorption rates with the compounds tested at the later time intervals. All compounds showed more than 85% dermal penetration within 5 days. At the early time intervals (greater than 24 h), penetration by the direct method was significantly greater for parathion and carbaryl than by the indirect method.

The Influence of Two Barrier Creams on the Percutaneous Absorption of m-Xylene in Man

Human volunteers were exposed to m-xylene by the percutaneous route (both hands immersed into the solvent for 20 minutes). The total amount of unchanged m-xylene eliminated through the respiratory tract during and after exposure and the total quantity of m-methylhippuric acid eliminated in urine during the subsequent 24 hours were measured. The majority of absorbed m-xylene (86 to 98%) is eliminated as m-methylhippuric acid in urine. The results obtained on eight subjects who repeated the test twice indicate that under similar experimental conditions the quantity of m-xylene absorbed percutaneously by an individual may vary with time by a factor of 2 or less. The interindividual variability in the total amount of m-xylene absorbed through the skin is greater than the intraindividual variability. Among 13 subjects, the ratio between the highest and the lowest value is 6.2; the mean percutaneous absorption rate of m-xylene amounts to 2.45 microgram/cm2 x min. The application of a barrier cream containing 10% silicone did not significantly influence the rate of percutaneous absorpiton of m-xylene by 11 subjects. Preliminary results obtained of five volunteers suggest that the application of a cream containing glycerol, stearates and oleostearates was not more effective.

PERCUTANEOUS ABSORPTION OF ORGANIC SOLVENTS

The percutaneous absorption of 8 chlorinated solvents were studied. The ex-perimental method consisted of the application of the solvent to the abdominal mouse skin and quantitating its absorption through the skin by its presence in whole body and its appearance in expiration. Determination of the solvent in tissues and expiration was carried out by gas chromatographic methods.There was a great diversity of ability among solvents to penetrate the mouse skin. Dichloromethane was absorbed to an amount which was 53 times as large as the amount of tetrachloroethyene. Among tested solvents, those which had the highest solubility in water showed the greatest absorption rate, while those having the lowest solubility in water gave the smallest absorption rate from skin. The linear relationship between the absorption rate from skin and the solubility in water was found: in case of X ?? 16, Y=30.8+2.13X, r=0.87; in case of X ?? 16, Y= -52.8+6.59X, r=1.00; where Y is the percutaneous absorption rate (nM/min/cm2 of skin) and X is the solubility in water of solvent (mM at 25°C).

PERCUTANEOUS ABSORPTION OF ORGANIC SOLVENTS

The percutaneous absorption of 8 chlorinated solvents were studied. The ex-perimental method consisted of the application of the solvent to the abdominal mouse skin and quantitating its absorption through the skin by its presence in whole body and its appearance in expiration. Determination of the solvent in tissues and expiration was carried out by gas chromatographic methods.There was a great diversity of ability among solvents to penetrate the mouse skin. Dichloromethane was absorbed to an amount which was 53 times as large as the amount of tetrachloroethyene. Among tested solvents, those which had the highest solubility in water showed the greatest absorption rate, while those having the lowest solubility in water gave the smallest absorption rate from skin. The linear relationship between the absorption rate from skin and the solubility in water was found: in case of X ?? 16, Y=30.8+2.13X, r=0.87; in case of X ?? 16, Y= -52.8+6.59X, r=1.00; where Y is the percutaneous absorption rate (nM/min/cm2 of skin) and X is the solubility in water of solvent (mM at 25°C).

The effect of glycerol on the percutaneous absorption of methyl nicotinate.

Summary.— The effect of glycerol on the rate of percutaneous absorption of methyl nicotinate from aqueous vehicles was investigated. The partition coefficients of methyl nicotinate between isopropyl myristate and aqueous solutions of glycerol were determined. The diffusivity of methyl nicotinate in various aqueous solutions of glycerol was also studied. It was shown that addition of glycerol in concentrations above 60% delayed the onset of erythema in human skin. The results suggest that this effect is related to the partition coefficient and diffusivity of methyl nicotinate in the aqueous vehicle. The osmotic effects of glycerol are negligible.

Value of Repeated Tests in a Percutaneous Absorption Study

Percutaneous absorption of salicylic acid was measured by blood levels in 20 rabbits, each given four runs at 1-week intervals. Dimethyl sulfoxide was added to the ointment in two runs (Runs 1 and 3 for half the animals, Runs 2 and 4 for the others), thus forming a crossover design with one repetition of each condition. The four successive runs caused a progressive and statistically, highly reliable decrease in percutaneous absorption. This effect of prior exposure increased during successive 1.5-hr, time intervals, from 1.5 to 7.5 hr., and showed no reliable interaction with dimethyl sulfoxide and with pH. A large effect of prior exposure was the increased stability of the salicylate absorption scores and, thereby, greater reliability of the experimental effects, shown by much lower residual terms in the analysis of variance for Runs 3 and 4 than for 1 and 2. Skin dehydration and decreased emotional arousal are possible explanations for the slower and more consistent rate of percutaneous absorption after prior exposure to the test situation.

Percutaneous Absorption of Trivalent and Hexavalent Chromium (<sup>51</sup>Cr) Through Excised Human and Guinea Pig Skin

The percutaneous absorption rate of trivalent (CrCl<sub>3</sub>) and hexavalent (Na<sub>2</sub>CrO<sub>4</sub>) chromium through excised human and guinea pig whole skin was determined by an isotope method (disappearance measurements). No difference in absorption between the compounds was observed. Thus, the lower absorption of CrCl<sub>3</sub>, obtained with the same method in vivo, could not be verified. The ratios between the <i>in vivo/in vitro</i> rates for CrCl<sub>3</sub> were lower than 1; for Na<sub>2</sub>CrO<sub>4</sub> they were concentration-dependent. The pH changes in chromium solutions after contact with guinea pig skin were greater <i>in vitro</i> than <i>in vivo</i>. Extrapolation of the results to <i>in vivo</i> conditions in man is not considered possible.

The Weights of Topical Preparations Required for Total and Partial Body Inunction

The results of dermatological research and therapy with topically applied medications are influenced by several factors among which the total amount applied and the specific area of application are important ones. These factors are often neglected or ignored in favor of concentration of active ingredient, rate of percutaneous absorption and frequency with which the preparations are applied. This disparity in emphasis has doubtless ensued because most topical treatments are performed by the subjects or patients and as such are at best indirectly controlled by the investigator.

Factors Influencing Percutaneous Absorption II: Absorption of Methyl Ethyl Ketone

A method is described for following the percutaneous absorption process with a vapor-phase chromatography technique. Data showing the absorption of methyl ethyl ketone (MEK) from a forearm surface of 91.5cm.² under both normal and hydrous conditions of the stratum corneum are presented. Hydration of the stratum corneum enhanced the percutaneous absorption rate of methyl ethyl ketone, but this penetrant subsequently partially dehydrated the stratum corneum. The resulting steady-state concentration of MEK in expired air, however, was still higher than that obtained with normal skin.

The Weights of Topical Preparations Required for Total and Partial Body Inunction

The results of dermatological research and therapy with topically applied medications are influenced by several factors among which the total amount applied and the specific area of application are important ones. These factors are often neglected or ignored in favor of concentration of active ingredient, rate of percutaneous absorption and frequency with which the preparations are applied. This disparity in emphasis has doubtless ensued because most topical treatments are performed by the subjects or patients and as such are at best indirectly controlled by the investigator.

Studies on the Percutaneous Absorption of Parathion and Paraoxon: Vi.In Vivo Decomposition of Paraoxon During the Epidermal Passage

In five earlier papers of this series various aspects of the percutaneous absorption of the well-known insecticide parathion (E 605, or diethyl 4-nitrophenyl thionophosphate) and its more toxic oxygen analogue paraoxon (E 600, or diethyl 4-nitrophenyl phosphate) were discussed. These studies covered such topics as the in vitro metabolism and enzymic degradation within the skin (8) the distribution of 32P-labelled parathion within the skin (2); the rate of absorption of parathion as investigated with the aid of labelled material and disappearance technic (3); decontamination of human skin from parathion (4); and also the rate of absorption of paraoxon (5). The method used in the last mentioned case was a dose-response technic, i.e. the rate of inhibition of plasma cholinesterase activity was determined following percutaneous absorption and continuous intravenous infusion in two separate groups of cats. The intravenous infusion was adjusted so that the rate of enzyme inhibition in plasma was approximately the same as following topical application. Since the rate of infusion and the area of absorption were known the rate of percutaneous absorption could easily be calculated.