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@ARTICLE{Benzel:176948,
      author       = {J. Benzel$^*$ and G. Bajraktari-Sylejmani and P. Uhl and A.
                      Davis and S. Nair and S. M. Pfister$^*$ and W. E. Haefeli
                      and J. Weiss and J. Burhenne and K. W. Pajtler$^*$ and M.
                      Sauter},
      title        = {{I}nvestigating the {C}entral {N}ervous {S}ystem
                      {D}isposition of {A}ctinomycin {D}: {I}mplementation and
                      {E}valuation of {C}erebral {M}icrodialysis and {B}rain
                      {T}issue {M}easurements {S}upported by {UPLC}-{MS}/{MS}
                      {Q}uantification.},
      journal      = {Pharmaceutics},
      volume       = {13},
      number       = {9},
      issn         = {1999-4923},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DKFZ-2021-02188},
      pages        = {1498},
      year         = {2021},
      note         = {#EA:B062#},
      abstract     = {Actinomycin D is a potent cytotoxic drug against pediatric
                      (and other) tumors that is thought to barely cross the
                      blood-brain barrier. To evaluate its potential applicability
                      for the treatment of patients with central nervous system
                      (CNS) tumors, we established a cerebral microdialysis model
                      in freely moving mice and investigated its CNS disposition
                      by quantifying actinomycin D in cerebral microdialysate,
                      brain tissue homogenate, and plasma. For this purpose, we
                      developed and validated an ultraperformance liquid
                      chromatography-tandem mass spectrometry assay suitable for
                      ultra-sensitive quantification of actinomycin D in the
                      pertinent biological matrices in micro-samples of only 20
                      µL, with a lower limit of quantification of 0.05 ng/mL. In
                      parallel, we confirmed actinomycin D as a substrate of
                      P-glycoprotein (P-gp) in in vitro experiments. Two hours
                      after intravenous administration of 0.5 mg/kg, actinomycin D
                      reached total brain tissue concentrations of 4.1 ± 0.7 ng/g
                      corresponding to a brain-to-plasma ratio of 0.18 ± 0.03,
                      while it was not detectable in intracerebral microdialysate.
                      This tissue concentration exceeds the concentrations of
                      actinomycin D that have been shown to be effective in in
                      vitro experiments. Elimination of the drug from brain tissue
                      was substantially slower than from plasma, as shown in a
                      brain-to-plasma ratio of approximately 0.53 after 22 h.
                      Because actinomycin D reached potentially effective
                      concentrations in brain tissue in our experiments, the drug
                      should be further investigated as a therapeutic agent in
                      potentially susceptible CNS malignancies, such as
                      ependymoma.},
      keywords     = {UPLC-MS/MS (Other) / actinomycin D (Other) / central
                      nervous system (Other) / cerebral microdialysis (Other) /
                      micro-sampling (Other)},
      cin          = {B062 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34575574},
      pmc          = {pmc:PMC8466300},
      doi          = {10.3390/pharmaceutics13091498},
      url          = {https://inrepo02.dkfz.de/record/176948},
}