In vitro human nail penetration and kinetics of panthenol.

The in vitro absorption of panthenol into and through the human nail was examined in this study. Panthenol, the alcohol form of pantothenic acid (vitamin B5), is believed to act as a humectant and improve the flexibility and strength of nails. A liquid nail treatment formulated with panthenol (2%) was compared to a solution of panthenol (2%) in water. Fingernail specimens were dosed daily for 7 days with either the nail treatment (non-lacquer film forming) formulation or aqueous solution with sampling performed every 24 h. Panthenol concentrations were determined in the dorsal surface, interior (by drilling and removal) and in the supporting bed under the human nail. Panthenol levels in the dorsal nail (R(2) = 0.87; P < 0.001), nail interior (R(2) = 0.94; P < 0.001) and nail supporting bed (R(2) = 0.79; P < 0.003) showed a significant linear increase with each day of dosing. Significantly more panthenol was delivered into the interior nail and supporting bed by a nail treatment formulation than from an aqueous solution. The film acts not only as a reservoir of panthenol, but also acts to increase the hydration of the nail and the thermodynamic activity of panthenol as well, thereby enhancing diffusion.

Topical bioavailability of a potential anti-acne agent (SC-23110) as determined by cumulative excretion and areas under plasma concentration time curves.

The topical bioavailability of a potential anti-acne agent ([14C]-SC-23110) was determined in the rhesus monkey, an animal model relevant to man. By the method of cumulative excretion in urine and feces the percutaneous absorption of 21 microgram/cm2 of the free base form was determined to be 0.58 +/- 0.16 (SD) percent of the applied dose. The mean areas under the plasma concentration time curves (AUC) following topical and intravenous administration were also determined. The ratior of the AUC's following topical and iv administration gave a bioavailability of 0.49% of the applied dose, a value in good agreement with the 0.58% obtained by cumulative excretion. Plasma AUC curves can be used to determined the percutaneous absorption (bioavailability) of compounds. Percutaneous absorption of [14C]-SC-23110 (80 microgram/cm2) when topically applied as the salt or free base form was compared. Twice the amount of compound was absorbed as the free base (0.34%) than as the salt (0.17%).

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.

Cutaneous metabolism of theophylline by the human skin.

Percutaneous absorption of theophylline in human skin from five sources was examined by use of a flow-through in vitro diffusion system. The metabolites and unchanged drug were estimated by thin-layer chromatography. Correlation was evident in the percentage of the applied dose that diffused through the five skin samples (range 2.8 +/- 0.5%-7.7 +/- 0.8%); however, the percentage of applied dose absorbed varied between different skin samples (range 3.6 +/- 0.9%-33.4 +/- 2.4%). Between 0.2 +/- 0.1%-4.6 +/- 0.2% of the doses applied were metabolized, and over 60% of the total metabolites formed diffused through the skin. The uptake and metabolism of theophylline by microsomes obtained from four of the human skin samples were measured. All preparations showed detectable activities for the metabolism of theophylline. Microsomal preparations from skin sources A, B, and E, and B, C, and E biotransformed theophylline to 1,3,7-trimethyluric acid and 1,3-dimethyluric acid, respectively. The activities of microsomes from skin samples C and E on the drug produced the pharmacologically active metabolite 3-methylxanthine. The specific activities of the microsomes from skin sources A-E for the formation of 1,3-dimethyluric acid and 3-methylxanthine varied fivefold. However, the variation in specific activities of the microsomes for the formation of 1,3,7-trimethyluric acid was twofold (range 2.8 +/- 0.1-6.2 +/- 0.5 pmol/min per mg protein). These metabolic data may be of value in the development of transdermal theophylline systems. The results indicate that a high level of absorption enhancement will be required before transdermal theophylline preparations could produce therapeutic plasma concentrations.

Minoxidil stimulates cutaneous blood flow in human balding scalps: pharmacodynamics measured by laser Doppler velocimetry and photopulse plethysmography.

In a double-blind study with randomly assigned topical solutions of 0%, 1%, 3%, or 5% minoxidil, the blood flow in balding scalps of 16 human volunteers was measured by the noninvasive techniques of both laser Doppler velocimetry (LDV) and photopulse plethysmography (PPG). On two consecutive days, an 0.25-ml volume of the assigned minoxidil formulation was spread uniformly over a 100-cm2 area of each side of the bald scalp and cutaneous blood flow was recorded for the following 4 h. Both measurement techniques showed that the 5% minoxidil solution stimulated the microcirculation of the bald scalp. Increased blood flow was greater with the 5% minoxidil solution than with the other treatments. Measured by LDV on day 1, the increase (p less than 0.0001) in blood flow occurred within 15 min of application of the 5% solution of minoxidil and was maintained at least through hour 1. On day 2, LDV showed blood flow stimulation with the 5% solution was 3-fold (p less than 0.0001) within 15 min of application and was so maintained for about 1 h. Measured by PPG, the only statistically significant (p less than 0.01) response occurred with the day 2 application of the 5% minoxidil solution. PPG is dependent on local blood volume and is only weakly correlated to cutaneous blood flow, which makes it unsuitable for this kind of study. Analysis of vital signs for days 1 and 2 revealed no systemic effect from treatment with minoxidil, suggesting that the blood flow stimulation was directly related to the topical application of minoxidil.

Percutaneous absorption of drugs.

The skin is an evolutionary masterpiece of living tissue which is the final control unit for determining the local and systemic availability of any drug which must pass into and through it. In vivo in humans, many factors will affect the absorption of drugs. These include individual biological variation and may be influenced by race. The skin site of the body will also influence percutaneous absorption. Generally, those body parts exposed to the open environment (and to cosmetics, drugs and hazardous toxic substances) are most affected. Treating patients may involve single daily drug treatment or multiple daily administration. Finally, the body will be washed (normal daily process or when there is concern about skin decontamination) and this will influence percutaneous absorption. The vehicle of a drug will affect release of drug to skin. On skin, the interrelationships of this form of administration involve drug concentration, surface area exposed, frequency and time of exposure. These interrelationships determine percutaneous absorption. Accounting for all the drug administered is desirable in controlled studies. The bioavailability of the drug then is assessed in relationship to its efficacy and toxicity in drug development. There are methods, both quantitative and qualitative, in vitro and in vivo, for studying percutaneous absorption of drugs. Animal models are substituted for humans to determine percutaneous absorption. Each of these methods thus becomes a factor in determining percutaneous absorption because they predict absorption in humans. The relevance of these predictions to humans in vivo is of intense research interest. The most relevant determination of percutaneous absorption of a drug in humans is when the drug in its approved formulation is applied in vivo to humans in the intended clinical situation. Deviation from this scenario involves the introduction of variables which may alter percutaneous absorption.

In vivo skin decontamination of methylene bisphenyl isocyanate (MDI): soap and water ineffective compared to polypropylene glycol, polyglycol-based cleanser, and corn oil.

In the home and workplace, decontamination of a chemical from skin is traditionally done with a soap-and-water wash, although some workplaces may have emergency showers. It has been assumed that these procedures are effective, yet workplace illness and even death occur from chemical contamination. Water, or soap and water, may not be the most effective means of skin decontamination, particularly for fat-soluble materials. This study was undertaken to help determine whether there are more effective means of removing methylene bisphenyl isocyanate (MDI), a potent contact sensitizer, from the skin. MDI is an industrial chemical for which skin decontamination, using traditional soap and water and nontraditional polypropylene glycol, a polyglycol-based cleanser (PG-C), and corn oil were all tried in vivo on the rhesus monkey, over 8 h. Water, alone and with soap (5% and 50% soap), were partially effective in the first h after exposure, removing 51-69% of the applied dose. However, decontamination fell to 40-52% at 4 h and 29-46% by 8 h. Thus, the majority of MDI was not removed by the traditional soap-and-water wash; skin tape stripping after washing confirmed that MDI was still on the skin. In contrast, polypropylene glycol, PG-C, and corn oil all removed 68-86% of the MDI in the first h, 74-79% at 4 h, and 72-86% at 8 h. Statistically, polypropylene glycol, PG-C, and corn oil were all better (p < 0.05) than soap and water at 4 and 8 h after dose application. These results indicate that a traditional soap-and-water wash and the emergency water shower are relatively ineffective at removing MDI from the skin. More effective decontamination procedures, as shown here, are available. These procedures are consistent with the partial miscibility of MDI in corn oil and polyglycols.

In vivo percutaneous absorption of boric acid, borax, and disodium octaborate tetrahydrate in humans compared to in vitro absorption in human skin from infinite and finite doses.

Literature from the first half of this century report concern for toxicity from topical use of boric acid, but assessment of percutaneous absorption has been impaired by lack of analytical sensitivity. Analytical methods in this study included inductively coupled plasma-mass spectrometry which now allows quantitation of percutaneous absorption of 10B in 10B-enriched boric acid, borax, and disodium octaborate tetrahydrate (DOT) in biological matrices. This made it possible, in the presence of comparatively large natural dietary boron intakes for the in vivo segment of this study, to quantify the boron passing through skin. Human volunteers were dosed with 10B-enriched boric acid, 5.0%, borax, 5.0%, or disodium octaborate tetrahydrate, 10%, in aqueous solutions. Urinalysis, for boron and changes in boron isotope ratios, was used to measure absorption. Boric acid in vivo percutaneous absorption was 0.226 (SD = 0.125) mean percentage dose, with flux and permeability constant (Kp) calculated at 0.009 microgram/cm2/h and 1.9 x 10(-7) cm/h, respectively. Borax absorption was 0.210 (SD = 0.194) mean percentage of dose, with flux and Kp calculated at 0.009 microgram/cm2/h and 1.8 x 10(-7) cm/h, respectively. DOT absorption was 0.122 (SD = 0.108) mean percentage, with flux and Kp calculated at 0.01 microgram/cm2/h and 1.0 x 10(-7) cm/h, respectively. Pretreatment with the potential skin irritant 2% sodium lauryl sulfate had no effect on boron skin absorption. In vitro human skin percentage of doses of boric acid absorbed were 1.2 for a 0.05% solution, 0.28 for a 0.5% solution, and 0.70 for a 5.0% solution. These absorption amounts translated into flux values of, respectively, 0.25, 0.58, and 14.58 micrograms/cm2/h and permeability constants (Kp) of 5.0 x 10(-4), 1.2 x 10(-4), and 2.9 x 10(-4) cm/h for the 0.05, 0.5, and 5.0% solutions. The above in vitro doses were at infinite, 1000 microliters/cm2 volume. At 2 microliters/cm2 (the in vivo dosing volume), flux decreased some 200-fold to 0.07 microgram/cm2/h and Kp of 1.4 x 10(-6) cm/h, while percentage of dose absorbed was 1.75%. Borax dosed at 5.0%/1000 microliters/cm2 had 0.41% dose absorbed, flux at 8.5 micrograms/cm2/h, and Kp was 1.7 x 10(-4) cm/h. Disodium octaborate tetrahydrate (DOT) dosed at 10%/1000 microliters/cm2 was 0.19% dose absorbed, flux at 7.9 micrograms/cm2/h, and Kp was 0.8 x 10(-4) cm/h. These in vitro results from infinite doses (1000 microliters/cm2) were 1000-fold greater than those obtained in the companion in vivo study. The results from the finite (2 microliters/cm2) dosing were closer (10-fold difference) to the in vivo results. General application of infinite dose percutaneous absorption values for risk assessment is questioned by these results. These in vivo results show that percutaneous absorption of boron, as boric acid, borax, and disodium octaborate tetrahydrate, through intact human skin, is low and is significantly less than the average daily dietary intake. This very low boron skin absorption makes it apparent that, for the borates tested, the use of gloves to prevent systemic uptake is unnecessary. These findings do not apply to abraded or otherwise damaged skin.

Utility of real time breath analysis and physiologically based pharmacokinetic modeling to determine the percutaneous absorption of methyl chloroform in rats and humans.

Due to the large surface area of the skin, percutaneous absorption has the potential to contribute significantly to the total bioavailability of some compounds. Breath elimination data, acquired in real-time using a novel MS/MS system, was assessed using a PBPK model with a dermal compartment to determine the percutaneous absorption of methyl chloroform (MC) in rats and humans from exposures to MC in non-occluded soil or occluded water matrices. Rats were exposed to MC using a dermal exposure cell attached to a clipper-shaved area on their back. The soil exposure cell was covered with a charcoal patch to capture volatilized MC and prevent contamination of exhaled breath. This technique allowed the determination of MC dermal absorption kinetics under realistic, non-occluded conditions. Human exposures were conducted by immersing one hand in 0.1% MC in water, or 0.75% MC in soil. The dermal PBPK model was used to estimate skin permeability (Kp) based on the fit of the exhaled breath data. Rat skin K(p)s were estimated to be 0.25 and 0.15 cm/h for MC in water and soil matrices, respectively. In comparison, human permeability coefficients for water matrix exposures were 40-fold lower at 0.006 cm/h. Due to evaporation and differences in apparent Kp, nearly twice as much MC was absorbed from the occluded water (61.3%) compared to the non-occluded soil (32.5%) system in the rat. The PBPK model was used to simulate dermal exposures to MC-contaminated water and soil in children and adults using worst-case EPA default assumptions. The simulations indicate that neither children nor adults will absorb significant amounts of MC from non-occluded exposures, independent of the length of exposure. The results from these simulations reiterate the importance of conducting dermal exposures under realistic conditions.

Assessment of the percutaneous absorption of trichloroethylene in rats and humans using MS/MS real-time breath analysis and physiologically based pharmacokinetic modeling.

The development and validation of noninvasive techniques for estimating the dermal bioavailability of solvents in contaminated soil and water can facilitate the overall understanding of human health risk. To assess the dermal bioavailability of trichloroethylene (TCE), exhaled breath was monitored in real time using an ion trap mass spectrometer (MS/MS) to track the uptake and elimination of TCE from dermal exposures in rats and humans. A physiologically based pharmacokinetic (PBPK) model was used to estimate total bioavailability. Male F344 rats were exposed to TCE in water or soil under occluded or nonoccluded conditions by applying a patch to a clipper-shaved area of the back. Rats were placed in off-gassing chambers and chamber air TCE concentration was quantified for 3-5 h postdosing using the MS/MS. Human volunteers were exposed either by whole-hand immersion or by attaching patches containing TCE in soil or water on each forearm. Volunteers were provided breathing air via a face mask to eliminate inhalation exposure, and exhaled breath was analyzed using the MS/MS. The total TCE absorbed and the dermal permeability coefficient (K(P)) were estimated for each individual by optimization of the PBPK model to the exhaled breath data and the changing media and/or dermal patch concentrations. Rat skin was significantly more permeable than human skin. Estimates for K(P) in a water matrix were 0.31 +/- 0.01 cm/h and 0.015 +/- 0.003 cm/h in rats and humans, respectively. K(P) estimates were more than three times higher from water than soil matrices in both species. K(P) values calculated using the standard Fick's Law equation were strongly affected by exposure length and volatilization of TCE. In comparison, K(P) values estimated using noninvasive real-time breath analysis coupled with the PBPK model were consistent, regardless of volatilization, exposure concentration, or duration.

Percutaneous absorption of hydrocortisone increases with long-term administration. In vivo studies in the rhesus monkey.

This study compares percutaneous absorption of hydrocortisone after short and long-term administration. The experimental design was to first apply 14C-hydrocortisone. This was followed by long-term administration of nonradioactive hydrocortisone. Then 14C-hydrocortisone was applied again when urinary excretion of radioactivity from the first application reached minimum detectable levels. Short- (first 14C-hydrocortisone application) and long-term (second 14C-hydrocortisone application) penetrations were compared. The level of absorption of hydrocortisone significantly increased during long-term administration, whether applied in an acetone vehicle or in a 0.9% emulsion ointment base (Eucerin). A placebo study in which only an acetone vehicle was applied for a long period followed by 14C-hydrocortisone application showed no enhanced penetration. It is suggested that long-term application of hydrocortisone alters the penetration barrier, resulting in enhanced penetration. The relevance of this long-term corticosteroid use in man is possibly of great importance.

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.

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.

Variations in percutaneous absorption of testosterone in the rhesus monkey due to anatomic site of application and frequency of application.

This study determines if the anatomic region affected percutaneous absorption in the rhesus monkey, an animal model with some relevance to man. Percutaneous absorption of testosterone (13.3 microgram/cm2) from the ventral forearm was 8.8 +/- 2.5%. Absorption from the chest was slightly less (5.3 +/- 0.6%) while that from the cheek was about the same (9.6 +/- 0.2%). Absorption from the scalp was greatly increased (20.4 +/- 2.7%), that from the vagina was the greatest (63.1 +/- 2.6%). As previously noted in man, anatomic variation in skin absorption exists in the rhesus. The ratio of scalp absorption to ventral forearm absorption in the rhesus was similar to that in man. The next objective was to determine the percutaneous absorption of testosterone when applied as a single dose or on a repetitive basis. There was no substantial difference in total absorption when 13.3 microgram/cm2 was applied as a single dose or when the 13.3 microgram/cm2 was applied three times, totaling 40 microgram/cm2. However, when 40 microgram/cm2 was applied as a single dose, absorption was substantially increased over 13.3 microgram/cm2 applied either once or three times. These results confirm previously reported results done with single versus repetitive doses of hydrocortisone.

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 mumol/cm2 14C-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.

Percutaneous penetration of hydrocortisone in humans following skin delipidization by 1:1:1 trichloroethane.

The effect of skin delipidization in humans on the percutaneous penetration of hydrocortisone was investigated in a cross-over trial. The delipidizing agent was 1:1:1 trichloroethane, a common industrial organic solvent. The findings do not show any significant difference in the topical absorption of hydrocortisone with and without skin delipidization. It was postulated that the natural skin barrier was reestablished by the metabolic cutaneous lipid regeneration concomitant with the absorption of the fatty ingredients from the cream.

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

The 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 less than arm less than chest less than thigh less than abdomen less than 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 less than 0.001).

Metabolism of 3-indolylacetic acid during percutaneous absorption in human skin.

This study assessed the in vitro percutaneous absorption and metabolism of 3-indolylacetic acid after topical dosing to human skin from four sources. The metabolism of the compound during percutaneous absorption was assessed. The absorbed and metabolized chemicals were analyzed by radioactive scintillation counting and thin-layer chromatography: 1.2% +/- 0.04%, 1.4% +/- 0.07%, 3.0% +/- 1.0%, and 0.1% +/- 0.02% of the applied doses permeated through human skin samples from sources A to D, respectively, whereas 3.4% +/- 0.5% to 20.0% +/- 0.2% of the applied doses were retained by the skin. Of the absorbed dose, 2.1% +/- 1.0% to 12.1% +/- 3.5% was present as metabolites in the receptor fluid, and 2.2% +/- 0.5% to 5.2% +/- 0.1% was present as metabolites retained in the skin. Microsomal fractions were prepared from the skin samples, and the actions of these preparations on 3-indolylacetic acid were estimated. 5'-Hydroxyl-3-indolylacetic acid, 5',6'-dihydroxy-3-indolylacetic acid, and 5,6-dihydroxyindole were formed both during percutaneous absorption and by skin microsomal preparations. In addition, the skin samples biotransformed the acid to metabolic indican (3-indoxylsulfuric acid) and to the glucuronide conjugate of indole. The possible functional significance of the metabolism is discussed.

Percutaneous absorption of azone following single and multiple doses to human volunteers.

Azone (1-dodecylazacycloheptan-2-one) is an agent that has been shown to enhance percutaneous absorption of drugs. Azone is thought to act by partitioning into skin lipid bilayers and thereby disrupting the structure. An open-label study was done with nine volunteers (two males, seven females; aged 51-76 years) in which Azone cream (1.6%; 100 mg) was topically dosed on a 5 x 10-cm area of the ventral forearm for 21 consecutive days. On days 1, 8, and 15, the Azone cream contained 47 microCi of [14C]Azone. The skin application site was washed with soap and water after each 24-h dosing. Percutaneous absorption was determined by urinary radioactivity excretion. The [14C]Azone was ring labeled [14C-2-cyclo-heptan]. Radiochemical purity was > 98.6% and cold Azone purity was 99%. Percutaneous absorption of the first dose (day 1) was 1.84 +/- 1.56% (SD) of applied dose for 24-h skin application time. Day 8 percutaneous absorption, after repeated application, increased significantly (p < 0.002) to 2.76 +/- 1.91%. Day 15 percutaneous absorption, after continued repeated application, stayed the same at 2.72 +/- 1.21%. In humans, repeated application of Azone results in an initial self-absorption enhancement, probably due to its mechanism of action. However, steady-state percutaneous absorption of Azone is established after this initial change. Thus, Azone can enhance its own absorption as well as that of other compounds. This should be considered relevant for any pharmacological or toxicological evaluation. Washing the skin site of application with soap and water only recovered 1-2% of applied radioactivity. Previous published studies recovered the Azone dose with ethanol washes. Thus, there could potentially be an accumulation of Azone in skin.

Pharmacokinetics and bioavailability of intravenous and topical nitroglycerin in the rhesus monkey: estimate of percutaneous first-pass metabolism.

[14C]Nitroglycerin was administered intravenously and topically to three rhesus monkeys and the pharmacokinetics were determined. The rhesus monkey is an animal model for which percutaneous absorption is similar to that in the human. After intravenous administration the decline in plasma nitroglycerin concentration was biexponential with an initial half-life of 0.8 min (2-5 min postadministration) and a terminal half-life of 18 min (5-60 min postadministration). After topical application in an ointment, plasma concentrations of unchanged nitroglycerin were first detectable at 0.25 hr postapplication. Peak plasma nitroglycerin concentrations occurred between 4-6 hr, and nitroglycerin was still detectable at 24 hr postapplication. Plasma levels fit a biexponential curve with an alpha-phase half-life of 3.0 hr, a beta-phase half-life of 4.3 hr, and a lag time of 0.5 hr. The absolute bioavailability of topical nitroglycerin was 56.6 +/- 5.8%. The differences in bioavailability estimates between unchanged nitroglycerin and total carbon-14 is considered to be the amount of nitroglycerin which is metabolized as it is absorbed through the skin (percutaneous first-pass effect). This value for topical nitroglycerin was quite small, only 16-21% depending on the method of comparison.