TY  - JOUR
AU  - Benzel, Julia
AU  - Bajraktari-Sylejmani, Gzona
AU  - Uhl, Philipp
AU  - Davis, Abigail
AU  - Nair, Sreenath
AU  - Pfister, Stefan M
AU  - Haefeli, Walter E
AU  - Weiss, Johanna
AU  - Burhenne, Jürgen
AU  - Pajtler, Kristian W
AU  - Sauter, Max
TI  - 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.
JO  - Pharmaceutics
VL  - 13
IS  - 9
SN  - 1999-4923
CY  - Basel
PB  - MDPI
M1  - DKFZ-2021-02188
SP  - 1498 
PY  - 2021
N1  - #EA:B062#
AB  - 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.
KW  - UPLC-MS/MS (Other)
KW  - actinomycin D (Other)
KW  - central nervous system (Other)
KW  - cerebral microdialysis (Other)
KW  - micro-sampling (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:34575574
C2  - pmc:PMC8466300
DO  - DOI:10.3390/pharmaceutics13091498
UR  - https://inrepo02.dkfz.de/record/176948
ER  -