Convective transport of highly plasma protein bound drugs facilitates direct penetration into deep tissues after topical application

Dancik, Yuri, Anissimov, Yuri G., Jepps, Owen G. and Roberts, Michael S. (2012) Convective transport of highly plasma protein bound drugs facilitates direct penetration into deep tissues after topical application. British Journal of Clinical Pharmacology, 73 4: 564-578. doi:10.1111/j.1365-2125.2011.04128.x


Author Dancik, Yuri
Anissimov, Yuri G.
Jepps, Owen G.
Roberts, Michael S.
Title Convective transport of highly plasma protein bound drugs facilitates direct penetration into deep tissues after topical application
Journal name British Journal of Clinical Pharmacology   Check publisher's open access policy
ISSN 0306-5251
1365-2125
Publication date 2012-04
Year available 2011
Sub-type Article (original research)
DOI 10.1111/j.1365-2125.2011.04128.x
Volume 73
Issue 4
Start page 564
End page 578
Total pages 15
Place of publication Oxford, United Kingdom
Publisher Wiley-Blackwell Publishing
Collection year 2013
Language eng
Formatted abstract
AIMS
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 4.5mm 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 1.1min for diclofenac and 30min 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.
Keyword Blood flow
Dermal absorption
Interstitial convection
Lipophilicity
Lymphatics
Protein binding
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Accepted Manuscript Published Online 14 October 2011.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Medicine Publications
 
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