Tacrolimus (TL) ointment is a topical treatment for atopic dermatitis, a disease that exhibits various skin conditions. The effect of skin pathologies on the systemic absorption of TL and related side effects remains unknown. This study aimed to investigate factors affecting the cutaneous absorption of TL. We prepared various skin models in hairless rats by tape stripping, injection of prophlogistic material solution (PMS), and continuous subcutaneous adrenaline (Adr) infusion. In vivo absorption studies were conducted, with measurements of transepidermal water loss (TEWL) and skin blood flow as physiological parameters. Very little TL absorption was observed through intact skin. Greater TL absorption was noted in skins with high TEWL values and fully stripped skin with PMS injections. In contrast, Adr infusion, which reduced skin blood flow, resulted in decreased TL absorption through fully stripped skin. Combined use of TL and Adr on skin with PMS injections resulted in suppression of TL absorption. Our results revealed that TL absorption following topical application is affected by alterations in the skin barrier, blood flow, and vascular permeability. We propose an administration plan for TL in a flowchart as a means of preventing systemic side effects.Key words tacrolimus; cutaneous absorption; atopic dermatitis; inflamed skin; transepidermal water loss; skin blood flow Tacrolimus (TL, FK506, molecular weight of 803.5) is a 23-membered macrolide lactone isolated from the bacterium Streptomyces tsukubaensis. For over two decades, TL has been widely used as a calcineurin inhibitor immunosuppressant for organ transplantation, given intravenously and orally. A topical formulation of TL (Protopic ® ointment, available in two TL ointment concentrations: 0.1% for adults and 0.03% for children) has also shown potent immunosuppressive activity and has been used as second line treatment for atopic dermatitis (AD) that cannot be controlled by topical corticosteroids.1,2) In 2006, the U.S. Food and Drug Administration (FDA) issued a black-box warning regarding a potential carcinogenic risk associated with TL ointment. Since then, some cohort studies and case-control studies have been conducted in order to reveal the association between topical use of TL and an increased risk of malignancy. Hui et al. and Arana et al. identified an increased risk of T-cell lymphoma with TL use.3,4) In contrast, other studies revealed no significant differences between TL use and non-use with regard to an increased risk of lymphoma.5,6) Due to short durations and potential study biases in these reports, results have been controversial. Thus, the FDA has advised that monitoring for occurrence of TL-related cancer be continued.AD is a chronically relapsing inflammatory skin disease with severe pruritus and eczema. The skin barrier function in AD patients is disrupted and exhibits an increase in transepidermal water loss (TEWL). [7][8][9] This skin disruption allows TL to permeate the skin despite a large molecular weight. 10,11) TL exerts ...

a long-term continuous use of TCIs causes skin atrophy and vasodilation, and attenuates the therapeutic effect of 1-1, Keyakidai, Sakado, Saitama 350-0295, Japan Jpn J Pharm Health Care Sci 43(9) 477-491 (2017) Tacrolimus (TL) is used topically for atopic dermatitis (AD) treatment. In AD, the skin shows various physiological alterations across individuals, body sites, and time-courses. Our previous study using rats showed that alterations in the skin barrier function and skin blood flow affected systemic absorption of topically applied TL. In this study, we performed an in vivo skin absorption study using NC/Nga mice repeatedly administered Dermatophagoides farinae extract as an AD animal model to assess skin barrier function and skin blood flow. We used three types of TL ointment: original TL ointment (Protopic ® 0.1 ointment) and liquid paraffin-diluted TL ointment with or without adrenaline (0.5 w /w ) to suppress systemic absorption of TL. Skin barrier function correlated positively with the systemic absorption of TL in AD skin as well as in tape-stripped rat skin, and dilution of TL ointment suppressed TL absorption and showed high skin TL retention. Although skin blood flow affected TL absorption as the skin barrier was disrupted, the distinct relationship among skin blood flow, TL absorption, and the effect of combined-use of adrenaline was unclear. The relationship between blood and skin disposition of TL was biphasic the ratio of blood to skin disposition increased rapidly at an inflection point. These results demonstrate that the dilution of TL ointment is useful for increasing treatment safety while retaining efficacy. The observed relationship between TL behavior and skin barrier function in AD model mice may also occur in AD patients and needs to be confirmed in further studies.