Pharmacokinetics and Biodistribution of Tacrolimus after Topical Administration: Implications for Vascularized Composite
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RESEARCH PAPER
Pharmacokinetics and Biodistribution of Tacrolimus after Topical Administration: Implications for Vascularized Composite Allotransplantation Firuz G. Feturi 1 & Jonas T. Schnider 2 & Paolo M. Fanzio 2 & Vasil E. Erbas 3 & Sinan Oksuz 4 & Huseyin Sahin 5 & Liwei Dong 6 & Jignesh M. Unadkat 2 & Alexander M. Spiess 2 & Jan A. Plock 7 & Mario G. Solari 2 & Vijay S. Gorantla 8 & Raman Venkataramanan 1 Received: 8 June 2020 / Accepted: 1 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT 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
Vijay S. Gorantla and Raman Venkataramanan contributed equally to this work. Vijay S. Gorantla and Raman Venkataramanan are the Co-Corresponding Authors * Vijay S. Gorantla [email protected] * Raman Venkataramanan [email protected] 1
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Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Room 4103, PTC 700 Technology Drive, Pittsburgh, Pennsylvania 15219, USA Department of Plastic and Reconstructive Surgery, School of Med
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