Abstract
Background and Objectives
TT-173 is the first topical hemostatic agent based on tissue factor. To prevent thromboembolic events and intravascular coagulation it is necessary to rule out the systemic absorption of new bioactive hemostats. Here, we radiolabeled TT-173 with [18F]SBF to characterize its systemic absorption and biodistribution.
Methods
A group of rats were administered intravenously with [18F]TT-173 and were subjected to a positron emission tomography study. A second group of animals received the [18F]TT-173 topically over a skin lesion in the flank. Topical absorption was quantified and the biodistribution patterns observed were compared.
Results
After topical application, low amounts of [18F]TT-173 were absorbed and distributed without relevant accumulation in any organ. On the other hand, after intravenous injection, [18F]TT-173 accumulated in lungs, liver and spleen, consistent with intravascular clot formation and the posterior capillary trapping and phagocytosis by the reticuloendothelial system. In both cases, a substantial concentration of radioactive product was found in urine consistent with renal excretion of degradation products of [18F]TT-173.
Conclusions
After topical application, [18F]TT-173 did not show a significant systemic accumulation in animal organs. Minor radioactive concentration found in lungs, liver and spleen likely corresponds with fragments of the product without procoagulant activity. Radiolabeling with [18F]SFB enables the characterization of systemic absorption and biodistribution of new topical hemostats like TT-173.
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Funding
This work has been funded by Thrombotargets Europe S.L. José Raúl Herance is hired by Fondo de Investigación Sanitaria. Instituto Carlos III. Under the program Miquel Servet I and the European Regional Development Fund (ERDF) CP13/00252.
Conflict of interest
José Raúl Herance and Juan D. Gispert have no conflicts of interest. The other authors are employed by Thrombotargets Europe S.L. However, the company does not have any commercial interest related with the publication of this work.
Ethical Approval
The experimental procedures were carried out following the European Directives and the Spanish Legislation regarding the use of animals for scientific purposes and with the specific approval of the Ethical Committee of Animal Experimentation of Barcelona Biomedical Research Park.
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S. Rojas and J. R. Herance equally contributed to the work.
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Rojas, S., Herance, J.R., Gispert, J.D. et al. Characterization of the Biodistribution and Systemic Absorption of TT-173, a New Hemostatic Agent of Recombinant Human Tissue Factor, Using Radiolabeling with 18F. Eur J Drug Metab Pharmacokinet 42, 583–592 (2017). https://doi.org/10.1007/s13318-016-0366-x
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DOI: https://doi.org/10.1007/s13318-016-0366-x