Aim

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).

Results

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.

Conclusion

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.

中文翻译：

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他克莫司局部给药后的药代动力学和生物分布：对血管化复合同种异体移植的影响。

目标

预防血管移植复合同种异体移植（VCA）后急性排斥反应（AR）所需的高剂量他克莫司（TAC）（1,2）与全身性不良反应有关。皮肤是VCA中最具抗原性的组织，也是AR的主要靶标。然而，短期使用局部TAC（Protopic®）作为口服TAC的标签外辅助剂治疗前列腺增生性AR发作（PRN），结果却不一致。缺乏有关VCA中局部TAC的药代动力学和组织分布的数据，这妨碍了我们对疗效不可靠的原因的理解。为了实现这一目标，我们评估了局部TAC在应用部位以低全身浓度实现高局部组织浓度的能力。

材料和方法

与大鼠全身给药后相比，我们评估了单次或多次局部应用后局部TAC（0.03％）的局部TAC的药代动力学和组织分布。动物以0.5 mg / kg的剂量接受TAC软膏的单次局部应用（组1）或TAC的静脉内（IV）注射（组2）。在另一项实验中，动物每天接受局部应用TAC软膏（第3组），或每天腹腔注射（IP）TAC（第4组），剂量为0.5 mg / kg，共7天。通过液相色谱-质谱法（LC / MS-MS）分析血液和组织中的TAC浓度。

结果

单次局部给药后，TAC吸收缓慢，Tmax为4小时，绝对生物利用度为11％。皮肤和肌肉中TAC的浓度比全血的浓度高出几倍。全身水平保持亚治疗水平（<3 ng / ml），每天重复使用一次。

结论

以0.5 mg / kg /天的剂量局部施用TAC软膏（Protopic®，0.03％）可在局部组织中提供高浓度而低全身暴露。反复局部施用TAC具有良好的耐受性，没有局部或全身性不良反应。这项研究证实了局部应用TAC局部应用TAC局部抑制TAC的可行性，并使将来在VCA中的应用成为可能。