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

Abstract

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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“…which is identical to that of actinomycin 0β (Supplementary Information Fig. S70-115, S-Table S7a-b) [52][53][54][55][56][57].…”

“…4a-m and Fig. 5) and HR-ESIMS, HR-LCMS, ESI-MS, QTRAP LC-MS/MS [52][53][54][55][56][57] (Fig. 5, S-Table S6), (Supplementary Information Fig.…”

Editorial: Cerebral microdialysis

“…In addition to examining the effects of therapies on brain metabolites in TBI or acute brain injury (i.e. stroke, aneurysmal subarachnoid hemorrhage), CMD has been used to examine the levels of chemotherapeutic and antibiotic agents in the brain (9)(10)(11). In the article by Sharma et al their figure 1 also emphasizes the extracellular space in the brain, which has received a great deal of attention lately in research on the glymphatic and dural lymphatic systems.…”