Differences in protein binding and excretion of Triapine and its Fe(III) complex

作者：Pelivan Karla; Miklos Walter; van Schoonhoven Sushilla; Koellensperger Gunda; Gille Lars; Berger Walter; Heffeter Petra^*; Kowol Christian R^*; Keppler Bernhard K

来源：Journal of Inorganic Biochemistry, 2016, 160: 61-69.

DOI：10.1016/j.jinorgbio.2015.10.006

• Drug development
• Thiosemicarbazones
• Triapine
• Pharmacokinetics
• In vivo

Triapine has been investigated as anticancer drug in multiple clinical phase I/II trials. Although promising anti leukemic activity was observed, Triapine was ineffective against solid tumors. The reasons are currently widely unknown. The biological activity of Triapine is strongly connected to its iron complex (Fe-Triapine) which is pharmacologically not investigated. Here, novel analytical tools for Triapine and Fe-Triapine were developed and applied for cell extracts and body fluids of treated mice. Triapine and its iron complex showed a completely different behavior: for Triapine, low protein binding was observed in contrast to fast protein adduct formation of Fe-Triapine. Notably, both drugs were rapidly cleared from the body (serum half-life time <1 h). Remarkably, in contrast to Triapine, where (in accordance to clinical data) basically no renal excretion was found, the iron complex was effectively excreted via urine. Moreover, no Fe-Triapine was detected in serum or cytosolic extracts after Triapine treatment. Taken together, our study will help to further understand the biological behavior of Triapine and its Fe-complex and allow the development of novel thiosemicarbazones with pronounced activity against solid tumor types.

• 出版日期2016-7