Dermal penetration prediction

Gute, B. D., Grunwald, G. D., Basak, S. C. Prediction of the dermal penetration of polycyclic aromatic hydrocarbons (PAHs) A hierarchical QSAR approach. SAR QSAR Environ. Res. 1999, 10, 1-15. 

Given the overwhelming influence of the physical properties of skin in determining bioavailabilities via the dermal route, assessment of dermal penetration is one area in metabolism and toxicology where in vitro methods can be effectively used to predict in vivo results and to screen chemicals. Apparatus and equipment exist that one can use to maintain sections of skin (obtained from euthanized animals or from human cadavers or surgical discard) for such experiments (Holland et al., 1984). These apparatus are set up to maintain the metabolic integrity of the skin sample between two reservoirs the one on the stratum comeum side, called the application reservoir and the one on the subcutaneous side, called the receptor reservoir. One simply places radiolabeled test material in the application reservoir and collects samples from the receptor fluid at various time points. 

Preliminary predictions of absorption of a substance can be made from its physico-chemical properties if no other information is available. Also elaborate computer programs are available that make predictions about, e.g., dermal penetration or metabolic pathways. However, these systems have often not been extensively validated against appropriate experimental data and it is not always certain if the results obtained in such models reflect the situation in vivo. On this basis, modeled data should only be used for risk assessment purposes where it is supported by other kinds of evidence. 

Although the oral route is the most common route of drug delivery, investigation into the prediction of uptake by other routes is also important. Dermal penetration and inhalation are not only relevant as methods of drug delivery, but in terms of toxicology they represent important routes of exposure. 

Gute, B.D., Grunwald, G.D. and Basak, S.C. (1999). Prediction of the Dermal Penetration of Polycyclic Aromatic Hydrocarbons (PAHs) A Hierarchical QSAR Approach. SAR QSAR Environ.Res., 10,1-15. 

Despite all their limitations, such predictions of skin permeability may be valuable and have several important potential uses. Ranking of drugs in order of potential dermal penetration is probably the most valuable use in the pharmaceutical field. For example, in situations where it is necessary to predict the dermal penetration potential for a series of homologous or closely related drugs, it is possible to rank the compounds using theoretical calculations. However, in order to validate the calculated values, it is essential to experimentally determine the skin permeation properties of several representative compounds of the group in a relevant vehicle. 

Additional field studies are needed for many application scenarios vhere data are limited. This will hopefully result in the further develc nent of useful predictive correlations. Improved methodology in the area of estimating hand exposure would be welcome. The data base for estimating dermal penetration also needs to be expanded. Finally, as Dr. Moraskl indicated earlier in his presentation, we need to know more about the effectiveness of various items of frotective clothing and protective devices. The use of protective clothing has been one of the chief regulatory options used in C >P in many of our recent deliberations. 

Although more predictive approaches may be possible in the future, with the ethical considerations of utilizing humans in studies with pesticides, currently the laboratory rat appears to be a suitable model. Dermal absorption studies with the rat allow the calculation of a penetration rate and hence, assist in the estimation of a potential body burden in man. Indeed, the extrapolation of a dermal penetration rate in the rat to man may represent a worst case approximation. Studies with one pesticide, malathion, in the rat and man have revealed the absorption/ penetration rate in the rat to be approximately 3-fold higher than man ( ). 

Recently, Riviere and Brooks (2007) published a method to improve the prediction of dermal absorption of compounds dosed in complex chemical mixtures. The method predicts dermal absorption or penetration of topically applied compounds by developing quantitative structure-property relationship (QSPR) models based on linear free energy relations (LFERs). The QSPR equations are used to describe individual compound penetration based on the molecular descriptors for the compound, and these are modified by a mixture factor (MF), which accounts for the physical-chemical properties of the vehicle and mixture components. Principal components analysis is used to calculate the MF based on percentage composition of the vehicle and mixture components and physical-chemical properties. 

Martin, A.D. (1990). A predictive model for the assessment of dermal exposure to pesticides, in Prediction of Percutaneous Penetration. Methods, Measurements, Modelling,... 

Ramsey, J.D., B.H. Woollen, T.R. Anton and R.C. Scott (1994). The predictive accuracy of in vitro measurements for the dermal absorption of a lipophilic penetrant (fluazifop-butyl) through rat and human skin. Fund. Appl. Toxicol, 23, 230-236. 

Naik, A., Keating, G. and Guy, R. H. Assessment of dermal exposure in humans. In Prediction of Percutaneous Penetration Methods, Measurements, Modelling. La Grande Mode STS Publishing Ltd., Cardiff, 1995. 

Since passive diffusion is the primary driving force behind dermal absorption, physicochemical factors such as molecular weight and structure, lipophilicity, pKa, ionization, solubility, partition coefficients, and diffusivity can influence the dermal absorption of various classes of chemicals. In addition penetration of acidic and basic compounds will be influenced by the skin surface, which is weakly acidic (pH 4.2-5.6), since only the uncharged moiety of weak acids and bases is capable of diffusing though the lipid pathway. Several of these factors (e.g., molecular weight, and partition coefficients) have been used to predict absorption of various drug classes [24-26],... 

Moody and Ritter, 1992 Wester et al., 1993). It describes a first-order relationship between mass of chemical in contact with the skin and penetration, but penetration is often a nonlinear fimction of applied dose. Percentage of dose absorbed can be used to predict total absorption for a different chemical concentration over the same surface area as long as exposure time is equivalent, such as the percentage absorbed at 24 h for both the original and the doubled dermal dose in Figure 6.3, which is nearly 100%. The percentage absorbed at 1 h would be about 25%. Percentage absorbed is dependent on exposure time therefore, it is not possible to accurately extrapolate to other exposure times. 

MNA) in PSFT models, for which permeability was less than predicted from log soMix> effect that carried into the IPPSF, suggesting a potential interaction with epidermal cells or dermal components, the only consistent factors different between isolated stratum comeum and SMFT compared to PSFT and IPPSF models. This interaction was also seen with other compounds. For PCP, stratum comeum partitioning appears to be the dominant factor. These findings support the hypothesis that a mixture component effect (such as SLS) in a specific solvent system will reduce permeability across penetrants (independent of the compound s specific QSPR relation to log K, ) and can be estimated by partition coefficients in simpler system. 

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... 

---