Pharmacokinetics and Biodistribution of Tacrolimus after Topical Administration: Implications for Vascularized Composite Allotransplantation


The high doses of oral tacrolimus (TAC) (1,2) necessary to prevent acute rejection (AR) after vascularized composite allotransplantation (VCA) are associated with systemic adverse effects. The skin is the most antigenic tissue in VCA and the primary target of AR. However, the short-term use of topical TAC (Protopic®), as an off-label adjunct to oral TAC, to treat AR episodes pro re nata (PRN), has yielded inconsistent results. There is lack of data on the pharmacokinetics and tissue distribution of topical TAC in VCA, that hampers our understanding of the reasons for unreliable efficacy. Toward this goal, we evaluated the ability of topical TAC to achieve high local tissue concentrations at the site of application with low systemic concentrations.

Materials and Methods

We assessed the pharmacokinetics and tissue distribution of topical TAC (Protopic®, 0.03%) after single or repeated topical application in comparison to those after systemic delivery in rats. Animals received a single topical application of TAC ointment (Group 1) or an intravenous (IV) injection of TAC (Group 2) at a dose of 0.5 mg/kg. In another experiment, animals received daily topical application of TAC ointment (Group 3), or daily intraperitoneal (IP) injection of TAC (Group 4) at a dose of 0.5 mg/kg for 7 days. TAC concentrations in blood and tissues were analyzed by Liquid Chromatography–Mass Spectrometry (LC/MS-MS).


Following single topical administration, TAC was absorbed slowly with a Tmax of 4 h and an absolute bioavailability of 11%. The concentrations of TAC in skin and muscle were several folds higher than whole blood concentrations. Systemic levels remained subtherapeutic (< 3 ng/ml) with repeated once daily applications.


Topical application of TAC ointment (Protopic®, 0.03%) at a dose of 0.5 mg/kg/day provided high concentrations in the local tissues with low systemic exposure. Repeated topical administration of TAC is well tolerated with no local or systemic adverse effects. This study confirms the feasibility of topical application of TAC for site specific graft immunosuppression and enables future applications in VCA.

Chemicals and Reagents

TAC powder, Cremophor EL (Kolliphor®), and ethanol were obtained from Sigma–Aldrich (St. Louis, MO, USA). TAC was prepared in a vehicle of 0.8% ethanol, 0.2% Cremophor EL (Kolliphor®), and saline solution (Sodium chloride, 0.9% w/v, USP) for IV or intraperitoneal (IP) administration at a final concentration of 1 mg of TAC/ml. For systemic delivery, TAC solution was administered at a volume of 0.15ml for a dose of 0.5 mg/kg body weight of rats (average body weight of 300 g). The amount of TAC ointment (Protopic®, 0.03%, 0.3 mg/g, Astellas, NJ) was calculated to be 0.5 g of ointment/rat for a dose of 0.5 mg of drug/kg body weight. This amount was estimated to be around 1 finger-tip unit [FTU] for a tube of Protopic ® with a 5 mm nozzle). (47–49) The ointment was applied evenly via a massaging motion on the hind limb of rat.

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Article Information: Feturi, F.G., Schnider, J.T., Fanzio, P.M. et al. Pharmacokinetics and Biodistribution of Tacrolimus after Topical Administration: Implications for Vascularized Composite Allotransplantation. Pharm Res 37, 222 (2020).

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