A physiological pharmacokinetic model for solute disposition in tissues below a topical application site

Purpose. Many compounds are applied to the skin with the aim of targeting d eeper underlying tissues. This work sought to define the pharmacokinetics o f solutes in tissues below a topical application site in terms of perfusate binding, tissue binding and perfusate flow rate. Methods. The disposition kinetics of diclofenac in a single pass perfused l imb preparation after dermal application disposition was studied using dext ran and bovine serum albumin (BSA) containing perfusates.;A pharmacokinetic model was then developed to relate the tissue retention half lives for dic lofenac, diazepam, water, lignocaine and salicylate to their fraction unbou nd in the tissues, their fraction unbound in the perfusate and the perfusat e flow rate. Results. Diclofenac had estimated tissue retention half lives of 18.1 hr an d 3.5 hr for the dextran and BSA containing perfusates, respectively. The f raction of diclofenac and other solutes unbound in the tissues correlated w ith their corresponding fraction unbound in the perfusate. The tissue reten tion half lives for diclofenac and other solutes could be described in term s of the fraction of solute unbound in the tissues and perfusate, together with the flow rate. Conclusion. The tissue pharmacokinetics of solutes below a topical applicat ion are a function of their binding in the tissues, binding in perfusate an d local blood flow.