%0 Journal Article
%A Benzel, Julia
%A Bajraktari-Sylejmani, Gzona
%A Uhl, Philipp
%A Davis, Abigail
%A Nair, Sreenath
%A Pfister, Stefan M
%A Haefeli, Walter E
%A Weiss, Johanna
%A Burhenne, Jürgen
%A Pajtler, Kristian W
%A Sauter, Max
%T Investigating the Central Nervous System Disposition of Actinomycin D: Implementation and Evaluation of Cerebral Microdialysis and Brain Tissue Measurements Supported by UPLC-MS/MS Quantification.
%J Pharmaceutics
%V 13
%N 9
%@ 1999-4923
%C Basel
%I MDPI
%M DKFZ-2021-02188
%P 1498 
%D 2021
%Z #EA:B062#
%X 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.
%K UPLC-MS/MS (Other)
%K actinomycin D (Other)
%K central nervous system (Other)
%K cerebral microdialysis (Other)
%K micro-sampling (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:34575574
%2 pmc:PMC8466300
%R 10.3390/pharmaceutics13091498
%U https://inrepo02.dkfz.de/record/176948