Pharmacokinetic Modeling

To assess the feasibility of the transdermal route for a specific therapeutic agent, several pharmacokinetic factors, including rate of absorption and elimination, must be considered. Guy and Hadgraft (59) developed an early kinetic model for topical drug delivery. Various rate constants were described including release rate from the device (first- or zero-order); back diffusion from the stratum corneum to the patch (usually insignificant); diffusion rates of the compound across the stratum corneum and viable epidermis; reverse rate constant (enabling prediction of the stratum cor-neum-viable epidermis partition coefficient) and the plasma clearance rate constant. This model has been used to predict the plasma concentration of several transder-mally administered drugs and has shown remarkable similarities between predicted and actual plasma concentration profiles, suggesting that the model is useful for evaluating the feasibility of potential transdermal drug delivery candidates.

Although this model provides predictive quantitative data based mainly on physicochemical and pharmacokinetic parameters, other aspects of the percutaneous absorption process are more difficult to predict. Of most concern is the potential for metabolic degradation of the drug, but only limited data are available on quantitative aspects of cutaneous metabolism. Modeling is possible, by estimating metabolic rate constants and varying the possible residence time of the drug in the skin. More lipophilic drugs, which have a relatively long residence time in the skin, will be more exposed to cutaneous metabolic enzymes and be less bioavailable than their hydrophilic counterparts.

More recent models for prediction of skin permeation and pharmacokinetics have become increasingly elaborate and take into account such parameters as the hydrogen-bonding capability of the permeant and potential vehicle effects (60).

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