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
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 free...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
17 September 2021
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| In: |
Pharmaceutics
Year: 2021, Volume: 13, Issue: 9, Pages: 1-16 |
| ISSN: | 1999-4923 |
| DOI: | 10.3390/pharmaceutics13091498 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/pharmaceutics13091498 Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/1999-4923/13/9/1498 
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| Author Notes: | Julia Benzel, Gzona Bajraktari-Sylejmani, Philipp Uhl, Abigail Davis, Sreenath Nair, Stefan M. Pfister, Walter E. Haefeli, Johanna Weiss, Jürgen Burhenne, Kristian W. Pajtler and Max Sauter |
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| 520 | |a 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. | ||
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