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000176948 1001_ $$0P:(DE-He78)2b12a7cfc604eb9816670e995f7af508$$aBenzel, Julia$$b0$$eFirst author$$udkfz
000176948 245__ $$aInvestigating the Central Nervous System Disposition of Actinomycin D: Implementation and Evaluation of Cerebral Microdialysis and Brain Tissue Measurements Supported by UPLC-MS/MS Quantification.
000176948 260__ $$aBasel$$bMDPI$$c2021
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000176948 520__ $$aActinomycin 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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000176948 650_7 $$2Other$$aUPLC-MS/MS
000176948 650_7 $$2Other$$aactinomycin D
000176948 650_7 $$2Other$$acentral nervous system
000176948 650_7 $$2Other$$acerebral microdialysis
000176948 650_7 $$2Other$$amicro-sampling
000176948 7001_ $$00000-0001-7870-1542$$aBajraktari-Sylejmani, Gzona$$b1
000176948 7001_ $$aUhl, Philipp$$b2
000176948 7001_ $$aDavis, Abigail$$b3
000176948 7001_ $$00000-0003-1286-4554$$aNair, Sreenath$$b4
000176948 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan M$$b5$$udkfz
000176948 7001_ $$00000-0003-0672-6876$$aHaefeli, Walter E$$b6
000176948 7001_ $$00000-0002-2034-923X$$aWeiss, Johanna$$b7
000176948 7001_ $$00000-0002-2190-1698$$aBurhenne, Jürgen$$b8
000176948 7001_ $$0P:(DE-He78)a7c1bbac024fa232d9c6b78443328d9d$$aPajtler, Kristian W$$b9$$udkfz
000176948 7001_ $$aSauter, Max$$b10
000176948 773__ $$0PERI:(DE-600)2527217-2$$a10.3390/pharmaceutics13091498$$gVol. 13, no. 9, p. 1498 -$$n9$$p1498 $$tPharmaceutics$$v13$$x1999-4923$$y2021
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