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This article reviews the literature pertinent to percutaneous absorption in the aged and compares the results to behavior seen in young adults. A well-defined function relating aging, percutaneous penetration, and the physicochemical properties of the transporting molecules is absent. Recent experimental approaches designed to resolve this dilemma and address the basic question are described and future areas for research are identified.

The in vitro release behavior of a novel liposome-based drug delivery device has been characterized. The system consists of a molded agarose matrix in which the model drug (progesterone) was dispersed either free or associated with one of four lipid formulations: egg-phosphatidylcholine (EPC) liposomes, EPC/cholesterol (2:1) liposomes, Intralipid® emulsion, and dipalmitoylphosphatidylcholine (DPPC) liposomes. Drug release rates from the devices into aqueous buffer were measured at 37° C. The free progesterone release rate decreased rapidly over 24 h with over 90% delivered. The liposomal patches, on the other hand, imposed apparent zero-order kinetics: for example, both the EPC and DPPC systems delivered their progesterone payloads at about 1%/h over 24 h. Further, the EPC and DPPC patches significantly slowed transdermal drug delivery across excised hairless mouse skin. The EPC device retarded throughput to one-half the control value, the DPPC system reduced the transport kinetics by an order of magnitude. The results support two hypotheses: (a) the liposomal-based reservoir system can modulate drug input via the skin, (b) the zero-order release of progesterone from liposomes is determined by slow interfacial transport out of the bilayer into the surrounding aqueous medium.

The relationship between pKa and skin irritation in humans was studied for a homologous series of benzoic acid derivatives with predicted permeation through human skin at comparable rates (15-90 μg/cm2/hr). Skin irritation and pKa are strongly correlated, and, for pKa ≤4, skin irritation rapidly increases. Laser Doppler velocimetric assessment of skin blood flow, color meter readings, erythema, edema, and the primary irritation index are all linearly correlated and related to pKa; erythema at 24 hr appears to be the most sensitive variable.

Diffusion equations were solved using the method of Laplace transformation to describe the flux of solutes across a model biological membrane. The theory is applicable to obtain either a permeability coefficient or an interfacial transfer rate constant. Previously published data were analyzed using the mathematical functions derived and the magnitude of the interfacial transfer coefficients discussed. These results may prove relevant to the general understanding of passive membrane transport as encountered in many model systems such as black lipid films and liposomes.

A linear pharmacokinetic model has been derived previously to analyze percutaneous absorption data. The model, which contains four first-order rate constants, has been extended to assess the effects of repeated topical dosing. It has been shown in previously published data that the amount of hydrocortisone excreted is dependent on the dosage regimen adopted. The model successfully describes the excretion pattern of hydrocortisone over a two-week period in which the drug was applied daily. Good correlation has also been established for the percutaneous penetration of malathion following repeated dosing. The patterns of the excretion profile for these two substances are different due to the difference in their physicochemical properties. These properties are reflected in the four first-order rate constants in the pharmacokinetic model.

To probe age-related changes in skin barrier function, transepidermal water loss (TEWL) rates have been measured in “young” (19–42 years) and “old” (69–85 years) subjects. TEWL was determined at ventral forearm skin sites, which had been occluded for 24 hr with polypropylene chambers. Baseline TEWL rates (J ∞, which showed no dependence on age, were measured for each subject before and after the experiment. Following removal of the occlusive chamber, TEWL was monitored continuously from t = 0.5 min until its return to the baseline (preocclusion) level, which was typically in the range of 2–7 g/m2/hr. Initial TEWL rates (mean ± SD) were found to differ significantly between young (28.6 ± 7.5 g/m2/hr; n = 26) and old (36.9 ± 10.5 g/m2/hr; n = 18) subjects (P < 0.01). Relaxation of TEWL to J ∞ was significantly slower in the aged cohort, such that the characteristic time for diffusion of water in the stratum corneum was estimated to be (mean ± SD) 176 ± 59 min for the young subjects, compared to 360 ± 76 min for the old (P < 0.001.). Thus, the initial TEWL value following removal of occlusion is significantly greater, and the excessive stratum corneum hydration produced by occlusion is dissipated more slowly, in old skin than in young. A hypothesis to explain the slower relaxation of perturbed TEWL in old skin is proposed.

The delivery of drugs via the skin to achieve systemic therapeutic effect is currently under intense investigation. The skin offers unique advantages and limitations for drug input into the body. For example, while hepatic first pass may be circumvented, the excellent barrier function of the stratum corneum (the thin outermost layer of skin) precludes, at present, all but the most potent drugs from this route of administration. Examples of approved transdermally delivered drugs are scopolamine, nitroglycerin, clonidine and estradiol. The delivery systems which have been formulated for these agents have been designed to provide essentially zero-order input kinetics for between 1 and 7 days. The impact of cutaneous metabolism on transdermal drug delivery has not yet been evaluated rigorously. Limited in vivo data for nitroglycerin suggest a cutaneous first pass effect of between 10 and 20%. More work has been directed towards the use of topical prodrugs and the design of molecules better able to transport across the stratum corneum and then undergo local enzymatic activation. Further research in this area will require a more specific quantitative understanding of the metabolic capabilities of human skin in vivo.

The release characteristics of aqueous and oily creams (BP) containing urea up to concentrations of 10% have been studied. The results show that the urea has little influence on the ability of the formulation to release its active ingredient, in this case, hexyl nicotinate. The preparations were then assessed in an in vivo experiment by measuring the time of onset of erythema induced by the hexyl nicotinate. The urea influenced the time of onset of erythema, and a mechanism for its action is proposed.

An actograph system was developed and used to record hourly locomotor activity for adult cabbage loopers, Trichoplusia ni (Hubner), soybean loopers, Pseudoplusia includens (Walker), velvetbean caterpillars, Anticarsia gemmatalis (Hubner), beet armyworms, Spodoptera exigua (Hubner), fall armyworms, S. frugiperda (J. E. Smith), and corn earworms, Heliothis zea (Boddie). The peak nocturnal activity of velvetbean caterpillars and corn earworms was greater than that of the other moths; and, except for these 2 species, males moved more often than females. Pairs were considerably less active and lived for fewer days than the isolated sexes.

A pharmacokinetic model to describe transdermal drug delivery has been developed. The rate constants in this approach have been assigned on the basis of the physicochemical parameters of the penetrant. The equations produced will allow the estimation of the plasma levels of the drug following the dermal application of a rate-controlling device. This simplified approach will not allow for rate control by the stratum corneum. The model has been used to calculate the theoretical levels of clonidine after it has been applied in a transdermal system.

The transport of two small organic solutes across a phospholipid barrier supported in a Millipore filter has been studied. The flux of penetrant across the barrier has been followed using two different experimental procedures with a rotating diffusion cell. In one approach, the data is analyzed by the normal reduction for rotating diffusion cell experiments; in the other, a new interpretation of the lag-time for transport across the barrier is invoked. The combination of the two analyses allows determination of the diffusion coefficient of the solute in the lipid barrier, the aqueous-lipid partition coefficient of the solute, and the interfacial transfer rate constant for the solute crossing the phospholipid-aqueous phase interface. Comparison of the transport parameters obtained with in vivo percutaneous absorption results is discussed.

Mathematical expressions have been derived which relate the degree of percutaneous penetration to the thickness of the applied base. The relative importance of simple physicochemical parameters is discussed and theoretical release curves provided to show the way in which optimum dosage regimens may be achieved.

A rotating diffusion cell has been used to determine the kinetics and thermodynamics associated with the transport of methyl nicotinate (3-pyridine-carboxylic acid, methyl ester) across an aqueous phase/ n -octanol liquid-liquid interface. The selection of the organic phase reflects the frequent successful use of octanol to simulate the properties of biomembranes and biophases in general. Hence the experiments are designed to probe, under carefully controlled conditions in the laboratory, a physicochemical event common to passive membrane transport and other pharmaceutically relevant partitioning processes. The results demonstrate that a significant free energy input is required for interfacial transfer and that the enthalpic and entropic contributions to the barrier depend upon the direction of partitioning. The kinetics of the liquid-liquid transfer process imply that interfacial transport has the potential to be rate-limiting in many biological and pharmaceutical systems.

Hydroquinone was found to penetrate readily human forehead skin in vivo following a single topical exposure, in an alcoholic vehicle, of 24 h duration. Percutaneous absorption was estimated using radiotracer methodology and 14C-labeled hydroquinone. The effects of a penetration enhancer, 1-dodecylazacycloheptan-2-one, and a sunscreen, the 2-ethylhexyl ester of 4-(dimethylamino)benzoic acid, on the percutaneous absorption of hydroquinone were investigated. In vivo penetration of hydroquinone was significantly decreased (a less than 0.05) by the addition of the 2-ethylhexyl ester of 4-(dimethylamino)benzoic acid (3% w/w) to the vehicle. The penetration enhancer, 1-dodecylazacycloheptan-2-one (0.5% w/w), did not significantly increase (a greater than 0.05) the absorption of hydroquinone. From all hydroquinone preparations, percutaneous absorption was rapid and peak elimination occurred within the first 12 h following application. Elimination was complete within 5 d.

The development of a physically based pharmacokinetic model for percutaneous absorption is described. The simulation includes four first-order rate constants assigned the following significance: (a) absorption across the stratum corneum; (b) diffusion through the viable tissue; (c) a retardation process which retains penetrant in the stratum corneum (and hence provides a means to mathematically produce a "reservoir" effect, for example); and (d) uptake from the skin into the systemic circulation and subsequent elimination from the body. The kinetic equations of the model are solved and expressions are obtained for the concentration of penetrant within the stratum corneum (and available to subsequently partition into the viable epidermis) and the plasma concentration of the administered substance, as a function of time. Using example values for the four rate parameters, disposition profiles for the penetrant in skin and plasma were derived. The cases considered cover slow and fast stratum corneum penetrants, substances which are excreted rapidly or slowly from the body, and absorbing molecules with a variety of relative stratum corneum-viable tissue affinities. The results suggest a framework for the prediction of pharmaceutically and clinically relevant information following the topical administration of therapeutic agents for local or systemic effect.

The relationship between pKa and skin irritation in man is studied for a homologous series of benzoic acid derivatives, which permeate through human skin at comparable rates (15–88 µg/cm2/hr). Skin irritation and pKa are correlated for pKa ≤ 4. Laser Doppler velocimetric assessment of skin blood flow, color meter readings, erythema, edema, and the primary irritation index are all linearly correlated and related to pKa, erythema at 24 hr appears to be the most sensitive parameter to variation in pKa when pKa ≤ 4.

Prediction of exposure and toxic potential of pesticides such as malathion are routinely based upon acute exposure and single-dose percutaneous absorption determination. What has become obvious with pesticide exposure such as the malathion spraying for the medfly is that chronic daily exposure is the more relevant situation. Our objective was to determine the percutaneous absorption of chronically applied malathion in man and to compare chronic absorption to single-dose absorption. The experimental design was to first topically apply [14C]malathion to human male volunteers. This procedure was followed by repeated administration of nonradioactive malathion to the same site of application (ventral forearm). [14C]Malathion was reapplied (Day 8) when urinary excretion of radioactivity from the first application reached minimum detectable levels. The first [14C]malathion absorption was compared to the second [14C]malathion application. The percutaneous absorption from the first [14C]malathion application was 4.48 +/- 1.3% (SD) of the applied dose. The absorption from the second [14C]malathion administration was 3.53 +/- 1.0%, a value not significantly (p greater than 0.05) different from the first application. Therefore, for malathion the single-dose application data are relevant for predicting the toxic potential for longer-term exposure.

A theoretical description of transdermal drug delivery has been developed using a straight-forward linear pharmacokinetic model. However, the rate constants in this model have been chosen such that they may be related to the physicochemical properties of the penetrant. Thus equations have been derived which may be used predictively to estimate the concentrations of drug in the plasma following transdermal application. The theoretical model has been used to predict plasma levels of scopolamine after this drug has been applied to the skin surface in a device that releases with zero order kinetics.

The surface of the skin supports a range of microorganisms capable of metabolizing some topically applied drugs. In order to ascertain the significance of this degradation we have established a mathematical model to predict the influence of this biotransformation on the plasma levels of the drug. The model is a linear kinetic representation of the process of skin absorption and the rate constants are predicted from a physicochemical consideration of the properties of the drug. The results of the simulations show that microbial degradation of the drug can be significant, particularly if the topical formulation is a thin film. If a transdermal device is used the theoretical calculations show that enzymatic degradation of the active substance is likely to be clinically less significant.

A kinetic model has been used to predict the plasma concentration vs time profiles for oestradiol, hyoscine and timolol following transdermal drug delivery. Rate constants describing a drug's passage across the stratum corneum and viable epidermis are calculated from simple physicochemical parameters. When used in conjunction with the in vitro release characteristics of the topical formulation (simple vehicle or sophisticated delivery system), and with knowledge of the drug's systemic clearance, the kinetic values permit simulation of the expected plasma level profile. The theoretical predictions are consistent with published human in vivo data for each of the three compounds. This kinetic approach may be useful, therefore, in the evaluation of feasible candidates for transdermal drug delivery.

The permeability barrier of hairless mouse skin has been determined in vitro after exposure of the epidermal surface to volumes of acetone typically used in human in vivo skin penetration studies. It has been shown that the transport of tritiated water (when applied for limited 5-h periods) across hairless mouse skin is not affected by acetone treatments of approximately 15 μl/cm 2 . Submersion of the membranes between aqueous donor and receptor phases for periods greater than 24 h, however, leads to significant and catastrophic barrier impairment. The acetone dose in the experiments reported is greater than that employed in vivo when the solvent is used to deposit a penetrant on human skin. We suggest, therefore, that acetone-mediated facilitation of percutaneous absorption in humans is unlikely. A further conclusion of this work is that in vitro solvent-deposition penetration experiments using hairless mouse skin should provide reliable transport information for at least 48 h postadministration. Although hairless mouse skin is more permeable than its human counterpart, in vitro measurements using the murine barrier should, therefore, provide useful and relevant guidelines for risk assessment calculations and bioavailability determinations.

Theoretical equations have been formulated to describe the effect of epidermal metabolic processes on the transport of drugs penetrating the skin. Michaelis-Menten kinetics have been assumed and the relative contributions from the kinetic parameters discussed.

During the process of adapting to a new rearing regime, laboratory and wild-type strains of the cabbage looper, Trichoplusia ni (Hubner), had similar survival and developmental rates but differed in reproductivity. A higher proportion of laboratory females mated, mated more frequently, and produced a greater average number of viable eggs. Successive generations of both strains had a parabolic curve of adult yields characterized by initial decline and subsequent recovery phases. Adaptation occurred by the F5 laboratory and F7 wild generations.

Sixteen compounds were coated on the paper surface of Kraft paper-aluminum foil laminated panels at deposits of 10, 50, or 100 mg per square foot. The compounds were evaluated for residual and vapor toxicity against the adult cigarette beetle, Lasioderma serricorne (F). Effectiveness was assessed by insect mortality after a 72-hour postexposure period. American Cyanamid 47300 ( O, O -dimethyl 0-4-nitro-mtolyl phosphorothioate) was effective both as a residual and as a vapor toxicant. Fenthion, Geigy 12968[ O, O -dimethyl phosphorodithioate, S-ester with 2-ethoxy-4-(mercaptomethyl)-△2-1,3,4-thiodiazolin-5-one], malathion, and Shell SD-9098 ( O -[2-chloro-l-(2,5-dichlorophenyl). vinyl] O, O -diethyl phosphorothioate) showed effective residual action. Compounds with effective vapor action were Bromodan [5-(bromomethyl)-1,2,3,4,7,7-hexachloro-2-norbornene], dichlorvos, lindane, Shell SD 9020 ( O -[2-chloro-1-(2,4-dichlorophenyl) vinyl] O, O -dimethyl phosphorothioate), and Velsicol 1-bromochlordene (1-bromo-4,5,6,7,8,8-hexachloro-3a,4,7,7a-tetrahydro-4,7-mcthanoindene). Compounds least toxic to the insects were DDT, pyrethrum-piperonyl butoxide, and carbaryl.

Ninety compounds structurally related to those compounds found in previous tests to be highly repellent to stored-product insects were evaluated as potential repellents of the red flour beetle, Tribolium castaneum (Herbst). Thirty-three of the 90 compounds were as repellent or more so than the pyrethrins-piperonyl butoxide combination used as a standard for comparison. Eight of 12 peroxycarbamic acid and 9 of 11 benzotriazin compounds tested were highly repellent to the test insect. N -Butylsulfenyl N, N -dimethyldithiocarbamate (peroxycarbamic acid, dimethyltrithio-, butyl ester) produced the highest average repellency recorded in standard repellency tests at this laboratory.

Objective measurements of blood flow changes following UV irradiation in the skin of human volunteers have been made with the noninvasive technique of laser Doppler velocimetry (LDV). This optical procedure allowed perfusion (number of red cells × velocity) alterations in the cutaneous microcirculation to be monitored after exposure of the skin to UVA and UVB + UVC radiation. Response curves were obtained in 6 subjects following irradiation at 4 times the minimal UVB + UVC erythema dose (MED). Measurements were made on control (untreated) skin and on skin pretreated with a sunscreen lotion. It was found that: (1) the lotion vehicle had no protective effect, (2) the active sunscreen constituent (2- ethyihexylcinnamate, 5%) was significantly protective, and (3) the presence of bergapten (5-methyoxypsoralen, 30 ppm) did not enhance or diminish the cinnamate protective effect. LDV measurements in 5 subjects were also taken during and subsequent to 5 daily exposures to 1 MED of UVB + UVC radiation. Control and pre -treated skin sites were again studied and similar protective effects were observed. However, on subsequent reexposure of these sites to 4 MED of UVB + UVC, 14 days after the first of the 5 single MED doses, no significant change in skin blood perfusion was detected at either control or pretreated sites. In a separate series of experiments, LDV data were collected after UVA radiation exposures up to 15 J/cm2. No changes in microcirculation perfusion were detected in any of the situations considered. All LDV measurements were made with 2 instruments of slightly different design and were compared to subjective assessments of erythema performed by a single observer. The results suggest that LDV has significant potential as a means to quantify (1) UV exposures in excess of the MED and (2) the inhibition of UV-induced changes in microcirculatory flow by chemical protectants.

Stratum corneum (SC), the outermost and least permeable layer of skin, is the major barrier to passive transepidermal water loss. In the research described in this paper, we have used human keratinocyte cultures, grown at the air-liquid (A/L) interface, to examine the relationship between epidermal differentiation (including SC formation) and barrier function. Histologically, the A/L culture showed several markets of complete differentiation, including the presence of well-organized and defined epidermal cell layers, keratohyalin granules, and a multilayered sc. The permeability of tritiated water through epidermal cultures, which had grown for 3 weeks at the A/L interface, was measured with a micro-diffusion apparatus. The results of these experiments demonstrated that: a) the human keratinocyte cultures developed a substantial barrier (i.e., a multilayered SC) to water diffusion across the entire surface. If the relative humidity of the culturing environment was lowered from 100% to around 75%, the barrier was significantly improved; b) the differentiation promoter, 1 ,25-dihydroxy-.vitamin-D 3 , increased the number of SC layers and reduced water permeation through the culture; c) the nature of the keratinocyte support matrix could be altered to improve the morphology as well as the barrier function of the epidermal cultures. Overall, the observations are consistent with the relationship that is believed to exist between SC intercellular lipid content and percutaneous penetration. confirmation of this hypothesis will further the considerable potential of human keratinocyte A/L cultures as a valuable and relevant model in which to study drug absorption and metabolism.

It is generally accepted that the stratum corneum (SC) is the least permeable layer of the epidermis. Histologically, though, the SC is a non-uniform, inhomogeneous membrane, and the question “Is barrier function distributed uniformly across the SC thickness?” has been posed. To address this issue, human ventral forearm SC has been studied in vivo by attenuated-total-reflectance Fourier-transform infrared spectroscopy during the course of sequential tape-stripping. Because the intercellular lipids of the SC and the degree of hydration of the membrane have been shown to be crucial determinants of barrier function, attention has been focused on the spectral features, which report specifically on these parameters. The degree of disorder of the SC intercellular lipids has been found to decrease over the outer cell layers (up to three tape-strips) and then to remain essentially constant. The amount of lipids decreases similarly such that a 60% reduction (relative to the “no-strip” baseline) is observed after about four tape-strips. A plausible explanation for these measurements is that the lipids near the surface are a mixture of (a) “true” intercellular lipid (which is expected to be highly ordered), and (b) sebaceous lipid (which contains much greater amounts of low-melting components, such as fatty acids). The sequential infrared (IR) spectra provide at least circumstantial evidence to support this hypothesis. As expected, the IR spectra show that SC hydration increases from the surface towards the SC-stratum granulosum interface. Taken together, the results imply that the SC is indeed non-uniform. The properties of the outer layers (those removed by the first 3-4 tape-strips) change significantly with increasing depth. Subsequently accessed layers (those revealed by tape-strips 5 through 14) imply that this deeper part of the barrier is relatively consistent throughout its thickness, with no evidence for a single, particularly resistant, component.

The objective of this work was to determine the pH gradient profile across hairless mouse stratum corneum (SC) using ratiometric laser scanning confocal microscopy imaging and direct pH measurement with a flat surface electrode. Dual-emission ratiometric imaging used the fluorophore, carboxy seminaphthorhodafluor1, which displays a pH-dependent shift in its emission spectrum. The assay developed was unsuccessful, however, because (i) the pKa of seminaphthorhodafluor (≈7.5) makes it insufficiently sensitive to the normal pH gradient (4–7.4) across mammalian SC, and (ii) the unexpectedly high buffering capacity of the skin precluded a meaningful calibration of the system. In the second method, pH measurements with a flat surface electrode were recorded as the hairless mouse SC was progressively tape stripped. In the superficial SC, the pH remained relatively constant (≈5.9); further removal of the barrier resulted in a steady increase in pH to ≈7. In conclusion, improved methodology is clearly required to characterize precisely the pH profile across the SC. Journal of Investigative Dermatology Symposium Proceedings 3:110–113, 1998

Noninvasive optical techniques of photopulse plethysmography (PPG) and laser Doppler velocimetry (LDV) have been used to identify regional variations in the basal skin blood flow of humans. The procedures assess either the volume (PPG) or the volume-velocity product (LDV) of cutaneous blood vessel perfusion. Fifty-two anatomic positions have been studied in 10 normal subjects resting horizontally. The mean perfusion levels were ranked to reveal the variations in cutaneous blood flow as a function of body site. Groups of data were collected into cohorts and average perfusion values for the subjects within each cohort were compared by the Newman-Keuls multiple comparison test. Most transparently, the results reveal a collection of regions (fingers, palms, face, ears) for which cutaneous perfusion is much higher than all other positions. More subtle differences and some unexpected similarities, however, are also apparent and, in some cases, agree or, in others, conflict, with previously published information. With some exceptions, good general agreement between the two techniques was observed.

Percutaneous penetration of the vasodilator methyl nicotinate (methyl 3-pyridinecarboxylate) has been monitored in vivo in humans with the noninvasive techniques of laser Doppler velocimetry and photopulse plethysmography. These optical methods use different technologies to generate a voltage output which is related to perfusion of the cutaneous microcirculation. The procedures are therefore sensitive to the pharmacologic stimulus and duration of local vasodilation. Following topical application of methyl nicotinate, excellent correlation was found between the response of both methods and the visual observation of erythema. Lower drug concentrations delayed the onset and magnitude of the response and shortened the time period for which elevated microperfusion was observed. These techniques appear to provide a useful noninvasive assessment of the time course of drug behavior in the region of skin to which topical application is made.

Theoretical expressions were derived that show how drug release rates are modified by sink and nonsink conditions. The effect of basic physicochemical parameters and the relevance to in vitro testing are discussed.

Description d'une technique de prelevement percutanee de substances, in vitro, par iontophorese inversee. Validation de la technique avec la clonidine, la theophylline et le glucose, sur peau de souris hairless

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.

Despite much research into the mechanisms of cutaneous aging and the identification of significant age-associated biological and biophysical changes within the skin, the question "How does aging affect percutaneous absorption (PA) in vivo?" remains unanswered. We have made in vivo measurements of PA in young (18-40 years) and old (greater than 65 years) subjects. Standard radiotracer methodology was employed and PA was quantified from the urinary excretion profiles of 14C radiolabel (corrected for incomplete renal elimination). Testosterone (TST), estradiol (EST), hydrocortisone (HC), benzoic acid (BA), acetylsalicylic acid (ASA), and caffeine (CAFF) have been studied. Permeation of HC, BA, ASA, and CAFF was significantly (p less than 0.01, 0.01, 0.01, and 0.05, respectively) lower in aged subjects, whereas the absorption of TST and EST was similar in the two groups. Thus it appears that aging can affect PA in vivo and that relatively hydrophilic compounds are particularly sensitive. The diminished surface lipid content of "old" skin implies a diminished dissolution medium for compounds administered topically. It is reasonable to speculate that this physiologic change will impact most severely upon those permeants whose lipid solubility is lowest (that is, HC, BA, ASA, CAFF). Furthermore, the typically reduced hydration of aged stratum corneum will compound this effect for these chemicals. Conversely, highly lipid-soluble chemicals (TST and EST) may still be able to dissolve readily into the stratum corneum even when the available lipid medium is reduced.

The response of human skin to topical methyl nicotinate (MN) has been monitored in black, oriental, and caucasian subjects. The study aimed to address the question: "Do racial differences in percutaneous absorption and microcirculatory sensitivity exist?" MN-induced vasodilatation was assessed visually and by laser Doppler velocimetry (LDV). At three dose levels, in the three subject populations, four parameters were compared: (a) the diameter of the maximum visually perceptible erythematous area (Emx); (b) the area under the erythematous diameter versus time curve (AUE); (c) the maximum LDV response (Lmax); and (d) the area under the LDV response versus time curve (AUL). At p less than 0.05, AUL (black) greater than AUL (caucasian) for all MN concentrations; AUL (oriental) greater than AUL (caucasian) for the higher dose levels. Emx, AUE and Lmx showed no significant differences between races within concentrations. For all subjects, Emx, AUE, and AUL were significantly dependent on MN dose whereas Lmx was not. The results suggest that some racial differences in response to topical MN exist and that perception of these distinctions may depend upon the method of measurement.

Evaluation of toxic exposure via the skin is invariably based upon forearm percutaneous absorption data and an appropriate area multiplication factor. Published experimental data clearly show, however, substantial site variation in skin penetration such that the use of forearm data may produce an inaccurate prediction of total body exposure. Using literature results for cutaneous absorption as a function of anatomic position and accepted estimations of human body surface areas, correction factors for use with forearm penetration data have been evaluated. Calculations have been performed for an adult, a small child and a neonate. Examples of limited exposure to specific regions of the body have also been assessed relative to predictions based upon percutaneous absorption across forearm skin. It appears that the use of forearm skin penetration data alone underestimates body exposure by at least a factor of two.

A biophysically based kinetic model of chemical absorption via human skin was developed and applied to the penetration kinetics of 12 chemicals: aspirin, benzoic acid, benzyl nicotinate, caffeine, chloramphenicol, colchicine, dinitrochlorobenzene, diethyltoluamide, malathion, methyl nicotinate, nitrobenzene, and salicylic acid. The pharmacokinetic model is linear and includes four first-order rate constants: (1) k1 describes penetrant diffusion through the stratum corneum; (2) k2 relates to further transport across the viable epidermal tissue to the cutaneous blood vessels; (3) k3 is a parameter which delays the partitioning of penetrant at the stratum corneum-viable tissue interface and, in conjunction with k2, reflects the penetrant's relative affinity for the stratum corneum over the viable tissue; and (4) k4 characterizes the elimination rate of chemical from blood to urine. Previously determined diffusion coefficients and molecular weight corrections were used to estimate k1 and k2; k4 values employed were those measured experimentally. Urinary excretion rate data following topical administration were simulated and k3 was estimated for each penetrant by optimizing the fit of the model to the data points. Ratios of k 3 k 2 should be related to the partition coefficients for the chemicals between stratum corneum and viable tissue and it was shown that these ratios agreed reasonably well with the corresponding octanol-water partition coefficients. This approach may have potential for predicting the general percutaneous absorption kinetics of chemicals based on recognized cutaneous biology and penetrant molecular weight and lipophilicity.

This review addresses the pharmacokinetics and pharmacodynamics of transdermally delivered drugs. The systemic input of drugs via the skin has attracted considerable interest over the past 15 years. The early promise of the administration route has, to some extent, been realised with the approval and successful launching of transdermal formulations of hyoscine (scopolamine), glyceryl trinitrate (nitroglycerin), clonidine and oestradiol. The further application of transdermal delivery, however, will require additional effort. While other molecules (e.g. testosterone, fentanyl, nicotine) may ultimately be administered in this way, important questions pertaining to pharmacology (tolerance), toxicity (irritation, sensitisation) and dose sufficiency (penetration enhancement) remain. These problems are illustrated using information which has been published in the literature. Overall, while the enthusiasm for attraction and benefits of transdermal delivery remain evident, it is clear that future successes will demand a heightened level of commitment and skill from the pharmaceutical scientist.