Effect of Physiological Changes in the Skin on Systemic Absorption of Tacrolimus Following Topical Application in Rats

Abstract

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 ...

Evaporative cooling provides a major metabolic energy sink

“…Typically, skin permeability assays are calibrated using positive controls such as acetone extraction or tape-stripping [21]. By way of illustration of the importance of the epidermal lipid barrier to water retention [31], we measured TEWL after an acetone wipe; this treatment increased water transpiration in our assay, in this case approximately 4-fold (Figure 3B).…”

Tear Film Pharmacokinetics and Systemic Absorption Following Topical Administration of 1% Prednisolone Acetate Ophthalmic Suspension in Dogs

“…Similarly, patients with ocular diseases may have a different PK profile or systemic absorption following topical corticotherapy, either related to ocular irritation (e.g., reflex tearing) and/or disruption of ocular barriers (e.g., denuded corneal epithelium or breakdown of the blood-tear barrier) (33,52). In fact, increased systemic absorption is well-documented for drugs administered topically on the inflamed skin (53,54). Ultimately, the aforementioned factors could be addressed by modeling tears and plasma prednisolone concentrations obtained from a large group of dogs, representing a population of diverse characteristics such as sex, age, and health status (55).…”

Preclinical Study of Tacrolimus Ointment for Prevention of Its Systemic Absorption in Atopic Dermatitis Model Mice According to Their Skin Conditions

“…In our previous study using rats, 31) skin blood flow correlated positively with systemic absorption of TL through fully SC-stripped skin. This suggests that a severely disrupted SC barrier results in TL skin permeation and that skin blood flow affects TL uptake into the blood stream.…”

“…In our previous study, 31) we performed an in vivo skin absorption study of TL in rats with physiologically altered skins. We prepared several skin models with different physiological conditions in hairless rats in order to separate the complex inflammatory responses into fundamental processes and evaluate their relationships with TL absorption.…”