title: Convective transport of highly plasma protein bound drugs facilitates direct penetration into deep tissues after topical application.
abstract: BACKGROUND
  Many products are applied to human skin for local effects in deeper tissues. Animal studies suggest that deep dermal and/or subcutaneous delivery may be facilitated by both dermal diffusion and transport via the cutaneous vasculature. However, the relationship between the extent and pathways of penetration, drug physicochemical properties and deeper tissue physiology is not well understood.
  
  
  CONCLUSIONS
  We have used a physiologically based pharmacokinetic model to analyze published human cutaneous microdialysis data, complemented by our own in vitro skin penetration studies. We found that convective blood, lymphatic and interstitial flow led to significant deep tissue concentrations for drugs that are highly plasma protein bound. In such cases, deeper tissue concentrations will occur earlier and may be several orders of magnitude greater than predicted by passive dermal diffusion alone.
  
  
  OBJECTIVE
  To relate the varying dermal, subcutaneous and muscle microdialysate concentrations found in man after topical application to the nature of the drug applied and to the underlying physiology.
  
  
  METHODS
  We developed a physiologically based pharmacokinetic model in which transport to deeper tissues was determined by tissue diffusion, blood, lymphatic and intersitial flow transport and drug properties. The model was applied to interpret published human microdialysis data, estimated in vitro dermal diffusion and protein binding affinity of drugs that have been previously applied topically in vivo and measured in deep cutaneous tissues over time.
  
  
  RESULTS
  Deeper tissue microdialysis concentrations for various drugs in vivo vary widely. Here, we show that carriage by the blood to the deeper tissues below topical application sites facilitates the transport of highly plasma protein bound drugs that penetrate the skin, leading to rapid and significant concentrations in those tissues. Hence, the fractional concentration for the highly plasma protein bound diclofenac in deeper tissues is 0.79 times that in a probe 4.5 mm below a superficial probe whereas the corresponding fractional concentration for the poorly protein bound nicotine is 0.02. Their corresponding estimated in vivo lag times for appearance of the drugs in the deeper probes were 1.1 min for diclofenac and 30 min for nicotine.
  
  
  CONCLUSIONS
  Poorly plasma protein bound drugs are mainly transported to deeper tissues after topical application by tissue diffusion whereas the transport of highly plasma protein bound drugs is additionally facilitated by convective blood, lymphatic and interstitial transport to deep tissues.
authors: Therapeutics Research Centre, School of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, QLD 4120, Australia.
authors: Yuri
authors: Y
authors: Dancik
authors: Yuri G
authors: YG
authors: Anissimov
authors: Owen G
authors: OG
authors: Jepps
authors: Michael S
authors: MS
authors: Roberts
mesh_terms: D000279:Administration, Cutaneous; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001692:Biological Transport; D001798:Blood Proteins / Q000378:metabolism; D004008:Diclofenac / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D009538:Nicotine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011485:Protein Binding; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D012869:Skin Absorption / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001798:Blood Proteins; D018722:Nicotinic Agonists; D004008:Diclofenac; D009538:Nicotine