Pharmacokinetic model percutaneous absorption

Conceptual models of percutaneous absorption which are rigidly adherent to general solutions of Pick s equation are not always applicable to in vivo conditions, primarily because such models may not always be physiologically relevant. Linear kinetic models describing percutaneous absorption in terms of mathematical compartments that have approximate physical or anatomical correlates have been proposed. In these models, the various relevant events, including cutaneous metabolism, considered to be important in the overall process of skin absorption are characterized by first-order rate constants. The rate constants associated with diffusional events in the skin are assumed to be proportional to mass transfer parameters. Constants associated with the systemic distribution and elimination processes are estimated from pharmacokinetic parameters derived from plasma concentration-time profiles obtained following intravenous administration of the penetrant. 

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. 

Williams PL, Carver MP, Riviere JE. A physiologically relevant pharmacokinetic model of xenobiotic percutaneous absorption utilizing the isolated perfused porcine skin flap (IPPSF). J Pharm Sci 1990 79 305-11. 

There have been three types of studies conducted in the IPPSF toxicology, percutaneous absorption (including biotransformation and pharmacokinetic modeling), and cutaneous drug distribution (drug administered by intraarterial infusion). The first two are discussed in this chapter. 

Qiao, G.L., Williams, PL., and Riviere, J.E., 1994, Percutaneous absorption, biotransformation and systemic disposition of parathion in vivo in swine. I. Comprehensive pharmacokinetic model. Drug Metab. Dispos., 22 459 71. 

Poet, T.S., Corley, R.A., Thrall, K.D., Edwards, J.A., Tranojo, H Weitz, K.K., Hui, X., Maibach, H.I., and Wester, R.C., 2000, Assessment of the percutaneous absorption of trichloroethylene in rats and humans using MS/MS real-time breath analysis and physiologically based pharmacokinetic modeling, Toxicol. Set, 56, 61-72. 

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. 

An ideal pharmacokinetic model of the percutaneous absorption process should be capable of describing not only the time course of penetration through skin and Into blood (or receptor fluid In a diffusion cell), but also the time course of disappearance from the skin surface and accumulation (reservoir effect) of penetrant within the skin membrane. Neither Pick s Plrst Law of Diffusion nor a simple kinetic model considering skin as a rate limiting membrane only Is satisfactory, since neither can account for an accumulation of penetrant within skin. To resolve this dilemma, we have analyzed the In vitro time course of absorption of radiolabeled benzoic acid (a rapid penetrant) and paraquat (a poor penetrant) through hairless mouse skin using a linear three compartment kinetic model (Figure 5). The three compartments correspond to the skin surface (where the Initial dose Is deposited), the skin Itself (considered as a separate compartment), and the receptor fluid In the diffusion cell. The Initial amount deposited on the skin surface Is symbolized by XIO, and K12 and K23 are first order rate constants. 

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