Percutaneous absorption predicting

Skin tape stripping can be used to determine the concentration of chemical in the stratum comeum at the end of a short application period (30 min) and by linear extrapolation predict the percutaneous absorption of that chemical for longer application periods. The chemical is applied to skin of animals or humans, and after a 30-minute skin contact application time, the stratum comeum is blotted and then removed by successive tape applications. The tape strippings are assayed for chemical content. There is a linear relationship between this stratum comeum reservoir content and percutaneous absorption. The major advantages of this method are (1) the elimination of urinary and fecal excretion to determine absorption and (2) the applicability to nonradiolabeled determination of percutaneous absorption, because the skin strippings contain adequate chemical concentrations for nonlabeled assay methodology. 

Transdermal drug delivery is an attractive route of drug administration and will continue to proliferate in the following years. In the developmental stages it is important to have predictive models and to be able to identify suitable drug candidates. Although still in its infancy, the approach described above can be used predictively and as the mechanisms involved in percutaneous absorption are better understood and quantified the model can be refined accordingly. 

In vivo studies have been conducted in man and in several species to compare absorption fates of numerous compounds. Percutaneous absorption rates in the rat and rabbit were generally higher than in human while the skin permeability of monkeys and swine more closely resembles humans. Although these differences are not predicted by any single factor, such as epidermal thickness, they are not unexpected in light of differences in skin characteristics. There are interspecies differences in routes of excretion of some chemicals as well. This may be due in part to metabolism of the... 

Riviere et al. (1999) used the isolated perfused porcine skin flap model to study absorption and disposition of JP-8. The percutaneous absorption and cutaneous disposition of topically applied neat Jet-A and JP-8 jet fuels were assessed by monitoring the absorptive flux of the marker components 14C naphthalene and 3H dodecane simultaneously. Absorption of 14C hexadecane was estimated from JP-8. Data were not reported in absolute amounts or concentrations. Instead, the objectives were to determine the relative absorption of the individual marker components from jet fuel, and the effect of a specific jet fuel s composition on the absorption of a specific marker. Having evaluated the absorption of only three of the 228 major nonadditive hydrocarbon constituents of the fuels, the authors stated that this is insufficient information to conduct risk assessments on jet fuels. However, the authors conclusions are informative. Naphthalene penetrated the skin more rapidly than dodecane or hexadecane, but the latter compounds had a larger fraction of the dose deposited in the skin. There were also differences in naphthalene and dodecane absorption and skin deposition between the fuels. These findings reinforce the difficulty of predicting risk for complex mixtures such as jet fuels. 

There are many different animal models that have been used to assess the percutaneous absorption of toxic chemicals. There is little question that while in vivo human studies are best for predicting the absorption of percutaneous applied chemical warfare agents, ethics preclude conducting such studies. Rats have been widely used in the study of skin contamination, wounds, and healing and the efficacy of different decontamination modalities (Wester and Maibach, 2000 Shah et al, 1987 Baynes et al., 1997). 

These linear kinetic models and diffusion models of skin absorption kinetics have a number of features in common they are subject to similar constraints and have a similar theoretical basis. The kinetic models, however, are more versatile and are potentially powerful predictive tools used to simulate various aspects of percutaneous absorption. Techniques for simulating multiple-dose behavior evaporation, cutaneous metabolism, microbial degradation, and other surface-loss processes dermal risk assessment transdermal drug delivery and vehicle effects have all been described. Recently, more sophisticated approaches involving physiologically relevant perfusion-limited models for simulating skin absorption pharmacokinetics have been described. These advanced models provide the conceptual framework from which experiments may be designed to simultaneously assess the role of the cutaneous vasculature and cutaneous metabolism in percutaneous absorption. 

Walker JD, Rodford R, Patlewicz G. Quantitative structure-activity relationships for predicting percutaneous absorption rates. Environ Toxicol Chem 2003 22 1870-84. 

Assessment of percutaneous absorption for any topically applied drug or chemical, can be classified based either on a model s level of biological complexity (in silico, in vitro, in vivo) or on the specific species studied (human, laboratory rodent, monkey, pig). The goal of the research should also be taken into consideration. Is the work being conducted to study the mechanism of absorption (e.g., identify a specific mathematical model or assess the effect of a vehicle) or to quantitatively predict absorption in humans Is the study designed to look at a local effect in skin or a systemic effect after absorption That is, are skin concentrations the relevant metric or is flux of chemical across skin important Model systems and approaches in use today to assess dermal absorption have recently been extensively reviewed [1]. 

The percutaneous absorption and dermatotoxicity of topically applied drugs and chemicals is a major concern in pharmacology, pharmaceutical, and toxicological sciences. As research in these areas continues and regulatory oversight is applied to more classes of substances, efforts have been made to develop predictive models to quantitate chemical exposure to the skin and systemic circulations. Model complexity increases with greater anatomical or physiological details. Before realistic predictive models can be constructed, experimental data must be collected of sufficient quality to make such efforts worthwhile. 

Skin-snake-model percutaneous absorption Relationships between the in vitro permeability of basic compounds through shed-snake skin as a suitable model membrane for human stratum corneum and their physio-chemical properties were investigated. Compounds with low pKa values were selected to compare the permeabilities of the nonionized forms of the compounds. Steady-state penetration was achieved immediately without a lag time for all compounds. Flux rate and permeability coefficient were calculated from the steady-state penetration data and relationships between these parameters and the physico-chemical properties were investigated. The results showed that permeability may be controlled by the lipophilicity and the molecular size of the compounds. Equations were developed to predict the permeability from the MWs and the partition coefficients of basic compounds. 

The 21-desoxy-16a,17a-isopropylidenedioxypregnenes 4 and 5 show potent anti-inflammatory properties and the allylic alcohol 6 has water solubility and a partition coefficient (water-ether) which might predict a favorable percutaneous absorption . 

In an ideal world, a large body of historical absorption data would allow a reasonably accurate prediction of the behaviour of a new drug based on previous experimental observations. However, after several decades of research and data accumulation, it is still only possible to make a rather limited approximation of the magnitude of the percutaneous absorption of a new drug from the permeability coefScient predicted using physicochemical properties (as described above). From this approximation, it is further necessary to approximate the potential total absorption for a given application regimen. 

Roberts, M. S. 1991. Structure-permeability considerations in percutaneous absorption. In Prediction of Percutaneous Penetration, vol. 2. Edited by R. C. Scott, R. H. Guy, J. Hadgraft, and H. E. Bodde. London IBC Technical Services, pp. 210-228. 

Rougier, A. 1987a. An original predictive method for in vivo percutaneous absorption studies. /. Soc. Cos-met. Chem. 38 397-417. 

Sartorelli, R, Aprea, C., Cenni, A., Novelli, M.T., Orsi, D., Palmi, S., and Matteucci, G., 1998, Prediction of percutaneous absorption from physiochemical data a model based on data of in vitro experiments. Aim. Occup. Hyg., 42 267-276. 

Silcox, G.D., Parry, G.E., Bunge, A.L., Pershing, L.K., and Pershing, D.W., 1990, Percutaneous absorption of benzoic acid across human skin. II. Prediction of an in vivo, skin-flap system using in vitro parameters, Pharm. Res., 7 352-358. 

Percutaneous absorption of topically applied substances is important in the fields of dermatotoxicology of chemicals that pose a threat to human exposure and of der-matopharmacology of drugs used to treat local or systemic medical disorders. Direct measurements of percutaneous absorption of compoimds in humans are often difficult because of ethieal issues and lack of sensitive analytical techniques. Many alternate animal models have been developed for in vivo prediction of dermal absorption. It is generally agreed that in vivo animal models should mimie anatomical, physiological, and biochemical similarities to humans as closely as possible so that extrapolation errors ean be minimized. However, direct measurements of dermal absorption in hiunans will remain the reference standard. 

Reifenrath, W.G., Chellquist, E.M., Shipwash, E.A., Jederberg, W.W., and Krueger, W.G., 1984, Percutaneous absorption in the hairless dog, weanling pig and grafted athymic nude mouse evaluation of models for predicting skin penetration in man, Br. J. Dermatol, lll(Suppl.), 27, 123-135. 

While it is difficult to predict the specific nature of the future suite of CB threats that will become available, all threats will most likely share three basic transport mechanisms - inhalation, ingestion, and percutaneous absorption of threat agent. Consequently, in all scenarios, the need exists to provide physical protection from aU three. Protection at this scale can be accomplished, in the future as today, by covering the entire body and providing adsorbent and particulate air filtration. Unlike current strategy, however, a future warrior uniform would not require the warrior to don additional layers for protection from CB threats, but it would rather provide that capability as an integral and transparent part of the standard uniform. 

Assessment of risk based on In vitro percutaneous absorption data depends on characterization of total penetrating amounts and of kinetic parameters which define the time course of absorption. Methods for determining these parameters have been reviewed. A pharmacokinetic model, which has the broad capability to predict not only the time course of absorption, but also the amounts accumulating within skin and remaining on the skin surface to be absorbed will be presented. Our results suggest that when a solid substance Is deposited on the skin surface from a volatile solvent, a fraction of the applied dose Is rapidly solubilized Into the skin faster absorption of this Initially solubilized fraction Is facilitated. 

An Ideal predictive description of the percutaneous absorption process should include not only the ability to predict the time course of the penetration process through the skin and absorption into the systemic circulation, but also an ability to predict the residual amounts remaining both on the skin surface and within the skin which are still available for absorption. In the latter half of this paper, a potentially useful pharmacokinetic model, which has this broad predictive capability, will be presented, together with data suggesting that solid substances deposited on the skin surface In volatile solvents are partially solubilized before the solvent has evaporated more rapid absorption of the solubilized fraction is then likely. 

Occupational disease, caused by skin contact with toxic substances, represents a major health problem In the United States (1). Dermal exposure of agricultural workers to pesticide agents, of course. Is a particularly pertinent example of this problem. Prediction of the detrimental toxic effects of hazardous chemical exposure Is difficult, however, because of the complexity of the percutaneous absorption process in man and a lack of any consistently Identifiable relatlonshlp(s) between transport rate and chemical properties. In addition, the very diverse approaches, which have been used to measure skin penetration, further complicate the situation since the extrapolation of results to man In his workplace may Involve questionable, non-valldated assumptions. Our specific aim Is to predict accurately the toxicokinetics of occupationally-encountered molecules (e.g., pesticides) absorbed across human skin In vivo. We present... 

---