title: A physiological pharmacokinetic model for solute disposition in tissues below a topical below a topical application site.
abstract: OBJECTIVE
  Many compounds are applied to the skin with the aim of targeting deeper underlying tissues. This work sought to define the pharmacokinetics of 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 limb preparation after dermal application disposition was studied using dextran and bovine serum albumin (BSA) containing perfusates. A pharmacokinetic model was then developed to relate the tissue retention half lives for diclofenac, diazepam, water, lignocaine and salicylate to their fraction unbound in the tissues, their fraction unbound in the perfusate and the perfusate flow rate.
  
  
  RESULTS
  Diclofenac had estimated tissue retention half lives of 18.1 hr and 3.5 hr for the dextran and BSA containing perfusates, respectively. The fraction of diclofenac and other solutes unbound in the tissues correlated with their corresponding fraction unbound in the perfusate. The tissue retention half lives for diclofenac and other solutes could be described in terms of the fraction of solute unbound in the tissues and perfusate, together with the flow rate.
  
  
  CONCLUSIONS
  The tissue pharmacokinetics of solutes below a topical application are a function of their binding in the tissues, binding in perfusate and local blood flow.
authors.affiliation: Department of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia. m.roberts@mailbox.uq.edu.au
authors.forename: M S
authors.initials: MS
authors.lastname: Roberts
authors.forename: S E
authors.initials: SE
authors.lastname: Cross
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D003911:Dextrans / Q000493:pharmacokinetics; D004008:Diclofenac / Q000493:pharmacokinetics*; D006207:Half-Life; D007700:Kinetics; D008297:Male; D017711:Nonlinear Dynamics; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D012044:Regression Analysis; D012710:Serum Albumin, Bovine / Q000493:pharmacokinetics; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects*; D012996:Solutions / Q000493:pharmacokinetics
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003911:Dextrans; D012996:Solutions; D004008:Diclofenac; D012710:Serum Albumin, Bovine