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| 024 | 7 | _ | |a 10.3390/pharmaceutics13091498 |2 doi |
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| 037 | _ | _ | |a DKFZ-2021-02188 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a Benzel, Julia |0 P:(DE-He78)2b12a7cfc604eb9816670e995f7af508 |b 0 |e First author |u dkfz |
| 245 | _ | _ | |a 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. |
| 260 | _ | _ | |a Basel |c 2021 |b MDPI |
| 336 | 7 | _ | |a article |2 DRIVER |
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| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1634042171_10606 |2 PUB:(DE-HGF) |
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| 500 | _ | _ | |a #EA:B062# |
| 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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| 650 | _ | 7 | |a UPLC-MS/MS |2 Other |
| 650 | _ | 7 | |a actinomycin D |2 Other |
| 650 | _ | 7 | |a central nervous system |2 Other |
| 650 | _ | 7 | |a cerebral microdialysis |2 Other |
| 650 | _ | 7 | |a micro-sampling |2 Other |
| 700 | 1 | _ | |a Bajraktari-Sylejmani, Gzona |0 0000-0001-7870-1542 |b 1 |
| 700 | 1 | _ | |a Uhl, Philipp |b 2 |
| 700 | 1 | _ | |a Davis, Abigail |b 3 |
| 700 | 1 | _ | |a Nair, Sreenath |0 0000-0003-1286-4554 |b 4 |
| 700 | 1 | _ | |a Pfister, Stefan M |0 P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9 |b 5 |u dkfz |
| 700 | 1 | _ | |a Haefeli, Walter E |0 0000-0003-0672-6876 |b 6 |
| 700 | 1 | _ | |a Weiss, Johanna |0 0000-0002-2034-923X |b 7 |
| 700 | 1 | _ | |a Burhenne, Jürgen |0 0000-0002-2190-1698 |b 8 |
| 700 | 1 | _ | |a Pajtler, Kristian W |0 P:(DE-He78)a7c1bbac024fa232d9c6b78443328d9d |b 9 |u dkfz |
| 700 | 1 | _ | |a Sauter, Max |b 10 |
| 773 | _ | _ | |a 10.3390/pharmaceutics13091498 |g Vol. 13, no. 9, p. 1498 - |0 PERI:(DE-600)2527217-2 |n 9 |p 1498 |t Pharmaceutics |v 13 |y 2021 |x 1999-4923 |
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