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Topical drug products are delivered to skin structures to treat numerous skin diseases. Due to the complexities of the skin environment and barrier, topical drug pharmacokinetics are difficult to determine, especially in vivo, as most pharmacokinetic assessment methods can only be performed ex vivo. Notably, in vivo conditions include perfusion via dermal capillaries, which influences topical drug uptake by acting as a clearance route and a "sink" driving permeation through the skin. In this study, we develop a method to examine the effects of perfusion on topical drug uptake in vivo using stimulated Raman scattering (SRS) microscopy, a chemically-specific imaging modality ideal for visualizing topical drug permeation over time. In this pilot study, we imaged the in vivo and ex vivo uptake of tazarotene in 70/30 v/v Transcutol:EtOH in paired mouse ear skin, comparing the effects of perfusion on tazarotene concentration (linearly proportional to SRS signal intensity) over time and pharmacokinetic parameters (T max , C max , AUC) in lipid-rich and lipid-poor regions in the stratum corneum and sebaceous glands. Obvious variations in SRS signal-time trends and statistically significant differences in stratum corneum pharmacokinetic parameters comparing uptake in lipid-rich and lipid-poor regions in vivo and ex vivo indicated slowed tazarotene flux through ex vivo skin in the absence of perfusion. The observed permeation differences in lipid-rich and lipid-poor regions in perfused and non-perfused skin reflects increased tazarotene permeation rate and removal in the presence of perfusion (in vivo) and decreased permeation rate and lack of elimination route in the absence of perfusion (ex vivo). Our method is demonstrated to be effective in assessing in vivo perfusion effects on topical drug uptake, promoting a better understanding of the influence of perfusion on topical drug delivery., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Conor Evans reports financial support was provided by Pfizer Inc. Conor Evans reports a relationship with Incyte Corporation that includes: funding grants and speaking and lecture fees. Conor Evans reports a relationship with 3M Company that includes: funding grants. Conor Evans reports a relationship with Petros Pharma that includes: funding grants. Conor Evans reports a relationship with Compass Skincare that includes: consulting or advisory. Conor Evans reports a relationship with Daxor Corporation that includes: consulting or advisory. Conor Evans reports a relationship with Avon Products Inc that includes: funding grants. Conor Evans reports a relationship with UNION therapeutics that includes: funding grants. Conor Evans reports a relationship with Intel Scientific that includes: funding grants. Conor Evans reports a relationship with Grey Global Group LLC that includes: funding grants. Alice Maciel Tabosa is currently employed by Certara. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

For topical drug products that target sites of action in the viable epidermal and/or upper dermal compartment of the skin, the local concentration profiles have proven difficult to quantify because drug clearance from the viable cutaneous tissue is not well characterised. Without such knowledge, of course, it is difficult-if not impossible-to predict a priori whether and over what time frame a topical formulation will permit an effective concentration of drug within the skin 'compartment' to be achieved. Here, we test the hypothesis that valuable information about drug disposition, and specifically its clearance, in this experimentally difficult-to-access compartment (at least, in vivo) can be derived from available systemic pharmacokinetic data for drugs administered via transdermal delivery systems. A multiple regression analysis was undertaken to determine the best-fit empirical correlation relating clearance from the skin to known or easily calculable drug properties. It was possible, in this way, to demonstrate a clear relationship between drug clearance from the skin and key physical chemical properties of the drug (molecular weight, log P and topological polar surface area). It was further demonstrated that values predicted by the model correlated well with those derived from in vitro skin experiments.