title: Self promotion of deep tissue penetration and distribution of methylsalicylate after topical application.
abstract: OBJECTIVE
  To determine how changes in cutaneous blood flow induced in-vivo by methylsalicylate (MeSA), compared to non-rubefacient triethanolamine salicylate (TSA), affected topical salicylate absorption and distribution, and to assess formulation therapeutic potential by comparing tissue concentrations to published antiinflammatory concentrations.
  
  
  METHODS
  Flux of salicylate from MeSA and TSA formulations applied to full-thickness rat skin was determined using in vitro diffusion cells. Anaesthetised rats were then used to quantify salicylate concentrations in plasma and tissues underlying the application site for the two formulations over a 6h period. In vitro and in vivo absorption profiles were then compared and the effect of MeSA on cutaneous blood flow assessed.
  
  
  RESULTS
  In vitro flux of salicylate from the MeSA formulation was 40% higher, though after correcting for differences in formulation concentrations the ratio of permeability coefficients was reversed. Contrary to the in vitro predictions, in vivo tissue and plasma concentrations of salicylate in rats rose rapidly in the first 1 hr and were more than the predicted 1.4-fold higher for MeSA. This effect was mirrored by the increase in blood flow induced by MeSA in human cutaneous vessels and that reported in the literature. Potential therapeutic levels were not seen below superficial muscle layers.
  
  
  CONCLUSIONS
  Direct tissue penetration of salicylate occurs below application sites from both MeSA and TSA formulations. Tissue concentrations of MeSA were higher than predicted due to its rapid distribution in the blood.
authors.affiliation: Department of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: S E
authors.initials: SE
authors.lastname: Cross
authors.forename: S A
authors.initials: SA
authors.lastname: Megwa
authors.forename: H A
authors.initials: HA
authors.lastname: Benson
authors.forename: M S
authors.initials: MS
authors.lastname: Roberts
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics; D017078:Laser-Doppler Flowmetry; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D012459:Salicylates / Q000493:pharmacokinetics*; D012869:Skin Absorption; D014018:Tissue Distribution
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D012459:Salicylates; C032758:trolamine salicylate; C033069:methyl salicylate