Uptake, translocation, and metabolization of amitriptyline, lidocaine, orphenadrine, and tramadol by cress and pea.

The uptake, translocation, and metabolization of four widely used drugs, amitriptyline, orphenadrine, lidocaine, and tramadol, were investigated in a laboratory study. Cress (Lepidium sativum L.) and pea (Pisum sativum L.) were employed as model plants. These plants were grown in tap water containing the selected pharmaceuticals at concentrations ranging from 0.010 to 10 mg L-1, whereby the latter concentration was employed for the (tentative) identification of drug-related metabolites formed within the plant. Thereby, mainly phase I metabolites were detected. Time-resolved uptake studies, with sampling after 1, 2, 4, 8, and 16 days, revealed that all four pharmaceuticals were taken up by the roots and further relocated to plant stem and leaves. Also in these studies, the corresponding phase I metabolites could be detected, and their translocation from root to stem (pea only) and finally leaves could be investigated.

Implementation of a comprehensive clinical risk management system in a university hospital.

BACKGROUND: Adverse events during hospital treatment are common and can lead to serious harm. This study reports the implementation of a comprehensive clinical risk management system in a university hospital and assesses the impact of clinical risk management on patient harms. METHODS: The clinical risk management system was rolled out over a period of eight years and consisted of a training of interdisciplinary risk management teams, external and internal risk audits, and the implementation of a critical incident reporting system (CIRS). The risks identified during the audits were analyzed according to the type, severity, and implementation of preventive measures. Other key figures of the risk management system were obtained from the annual risk reports. The number of liability cases was used as primary outcome measurement. RESULTS: Of the 1,104 risks identified during the risk audits, 56.2% were related to organization, 21.3% to documentation, 15.3% to treatment, and 7.2% to patient information and consent. The highest proportion of serious risks was found in the category organization (22.7%), the lowest in the category documentation (13.6%). Critical incident reporting identified between 241 and 370 critical incidents per year, for which in 79.5% to 83% preventive measures were implemented within twelve months. The frequency of incident reports per department correlated with the number of active risk managers and risk team meetings. Compared with the years prior to the introduction of the clinical risk management system, an average annual reduction of harms by 60.1% (95% CI: 57.1; 63.1) was observed two years after the implementation was completed. On average, the rate of harms dropped by 5% per year for each 10% increase in roll-out of the clinical risk management system (incidence rate ratio: 0.95; 95% CI: 0.93; 0.97) . CONCLUSION: The results of this project demonstrate the effectiveness of clinical risk management in detecting treatment-related risks and in reducing harm to patients.

Determination of the Influence of Multiple Closed Recycling Loops on the Property Profile of Different Polyolefins.

In a circular economy, polymeric materials are used in multiple loops to manufacture products. Therefore, closed-loops are also envisaged for the mechanical recycling of plastics, in which plastic is used for products that are in turn collected and reprocessed again and again to make further products. However, this reprocessing involves degradation processes within the plastics, which become apparent through changes in the property profile of the material. In the present paper, the influence of multiple recycling loops on the material properties of four different polyolefins was analyzed. Two different closed-loop cycles with industrially sized processing machines were defined, and each polyolefin was processed and reprocessed within the predefined cycles. For the investigation of the effect of the respective loops, samples were taken after each loop. The samples were characterized by high-pressure liquid chromatography coupled to a quadru-pole time-of-flight MS, high-temperature gel permeation chromatography, melt flow rate measurements, infrared spectroscopy, differential thermal analysis, and tensile tests. With increasing number of processing loops, the tested polyolefins showed continuous material degradation, which resulted in significant changes in the property profiles.

Plasma Metabolomic Profiling Reveals Four Possibly Disrupted Mechanisms in Systemic Sclerosis.

Systemic sclerosis (SSc) is a rare systemic autoimmune disorder marked by high morbidity and increased risk of mortality. Our study aimed to analyze metabolomic profiles of plasma from SSc patients by using targeted and untargeted metabolomics approaches. Furthermore, we aimed to detect biochemical mechanisms relevant to the pathophysiology of SSc. Experiments were performed using high-performance liquid chromatography coupled to mass spectrometry technology. The investigation of plasma samples from SSc patients (n = 52) compared to a control group (n = 48) allowed us to identify four different dysfunctional metabolic mechanisms, which can be assigned to the kynurenine pathway, the urea cycle, lipid metabolism, and the gut microbiome. These significantly altered metabolic pathways are associated with inflammation, vascular damage, fibrosis, and gut dysbiosis and might be relevant for the pathophysiology of SSc. Further studies are needed to explore the role of these metabolomic networks as possible therapeutic targets of SSc.

Simultaneous analysis of quaternary ammonium cations and corresponding halide counterions by pyrolysis gas chromatography / mass spectrometry.

The use of quaternary ammonium compounds (QACs) as disinfectants has increased tremendously in the COVID-10 pandemic to inactivate Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV2). Dialkyldimethylammonium halides represent a frequently used type among QACs. Different halide anions, each ionically linked to the same quaternary ammonium cation, show clear differences in biocidal activity, toxicity and allergic potential. Likewise, the alkyl chain length at the ammonium cation induces different biocidal efficacy and toxicology. Therefore, the object of this research was to develop a rapid and reliable method for the detection of ammonium cation and halide anion in a single analytical run. For that purpose, a gas chromatography mass spectrometry (GC/MS) method was developed for QACs of the dialkyldimethylammonium type. Pyrolytic conversion of the QACs in the injector port of the gas chromatograph into volatile molecule species allows fast and reliable subsequent GC/MS analysis. The developed method is suited for the determination of both the quaternary ammonium cation and the corresponding halide anion in a single gas chromatographic run. The application of this method to bulk material and standard material of explicitly specified didecyldimethylammonium chloride revealed deviations from the manufacturer's specifications in a range up to four-fifths. Furthermore, didecyldimethylammonium chloride was detected in a disinfectant that does not comply with the labeling requirement for biocidal ingredients. With the method presented, results can be obtained for disinfectants with minimum effort within seven minutes.

Comparison of one-phase and two-phase extraction methods for porcine tissue lipidomics applying a fast and reliable tentative annotation workflow.

Lipidomics has great potential for the discovery of biomarkers, elucidation of metabolic processes and identifying dysregulations in complex biological systems. Concerning biofluids like plasma or cerebrospinal fluid, several studies for the comparison of lipid extraction solvents have already been conducted. With respect to tissues, which can differ significantly in terms of dry matter content and composition, only few studies are available. The proper selection of an extraction method that covers the complexity and individuality of different tissues is challenging. The goal of this work was to provide a systematic overview on the potential of different extraction methods for a broad applicability. This study covers six different extraction procedures and four different reconstitution solvents applied to ten different porcine tissues. To get an overview of the individual lipid profiles, a workflow was developed for a fast and reliable tentative lipid annotation. Therefore, several machine learning tools were utilized, like the prediction of collision cross sections to support the tentative lipid identification in case of untargeted lipidomics. In terms of data evaluation, unsupervised (e.g. principal component analysis) and supervised (e.g. partial least square - discriminant analysis) methods were applied to visualize and subsequently interpret all generated information. Furthermore, the influence of the tissue composition on the extraction performance was investigated. It could be shown that the ten porcine tissues can be distinguished based on their lipid profile with the applied workflow and that the methyl-tert-butyl ether (MTBE) based extraction method (two-phase) showed the best overall performance for the 16 examined lipid species. With this method the highest number of features (428 in lung tissue) could be annotated. Upcoming one-phase extractions also showed a high potential concerning total number of extracted lipids. Methanol/MTBE/chloroform (MMC) extracted slightly less lipids (393 in lung and liver) than MTBE but turned out to be the best one-phase extraction method. Additionally, the numbers of extracted lipids obtained by isopropanol/water 90:10 (IPA90) (399 in stomach) and by isopropanol/methanol/chloroform (IMC) (395 in stomach) were similar to those of the modified Folch method (402 in stomach). One-phase extractions can therefore clearly be seen as preferable when a high throughput is needed.

Large-Scale Evaluation of Collision Cross Sections to Investigate Blood-Brain Barrier Permeation of Drugs.

Successful drug administration to the central nervous system requires accurate adjustment of the drugs' molecular properties. Therefore, structure-derived descriptors of potential brain therapeutic agents are essential for an early evaluation of pharmacokinetics during drug development. The collision cross section (CCS) of molecules was recently introduced as a novel measurable parameter to describe blood-brain barrier (BBB) permeation. This descriptor combines molecular information about mass, structure, volume, branching and flexibility. As these chemical properties are known to influence cerebral pharmacokinetics, CCS determination of new drug candidates may provide important additional spatial information to support existing models of BBB penetration of drugs. Besides measuring CCS, calculation is also possible; but however, the reliability of computed CCS values for an evaluation of BBB permeation has not yet been fully investigated. In this work, prediction tools based on machine learning were used to compute CCS values of a large number of compounds listed in drug libraries as negative or positive with respect to brain penetration (BBB+ and BBB- compounds). Statistical evaluation of computed CCS and several other descriptors could prove the high value of CCS. Further, CCS-deduced maximum molecular size of BBB+ drugs matched the dimensions of BBB pores. A threshold for transcellular penetration and possible permeation through pore-like openings of cellular tight-junctions is suggested. In sum, CCS evaluation with modern in silico tools shows high potential for its use in the drug development process.

Changes in Plasma Phospholipid Metabolism Are Associated with Clinical Manifestations of Systemic Sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease with fibrosis of the skin and/or internal organs, causing a decrease in quality of life and survival. There is no causative therapy, and the pathophysiology of the SSc remains unclear. Studies showed that lipid metabolism was relevant for autoimmune diseases, but little is known about the role of lipids in SSc. In the present study, we sought to explore the phospholipid profile of SSc by using the lipidomics approach. We also aimed to analyze lipidomics results for different clinical manifestations of SSc. Experiments were performed using high-performance liquid chromatography coupled to mass spectrometry for the lipidomic profiling of plasma samples from patients with SSc. Our study showed, for the first time, significant changes in the level of phospholipids such as plasmalogens and sphingomyelins from the plasma of SSc patients as compared to controls. Phosphatidylcholine plasmalogens species and sphingomyelins were significantly increased in SSc patients as compared to controls. Our results also demonstrated a significant association of changes in the metabolism of phospholipids (phosphatidylcholine and phosphatidylethanolamine plasmalogens species and sphingomyelins) with different clinical manifestations of SSc. Further lipidomic studies might lead to the detection of lipids as new biomarkers or therapeutic targets of SSc.

Discrepancies in the German Pharmacopoeia procedure for quality control of Quillaja saponin extracts.

This study focused on the evaluation of Quillaja saponin extracts with the additional quality designation DAB-which means the abbreviation of the German Pharmacopoeia (Deutsches Arzneibuch). This label suggests that Quillaja saponin extracts marked in this way are of pharmacopoeial quality and thus stand out from other Quillaja saponin extracts. The DAB ninth edition listed Quillaia saponin as a reagent. According to DAB, its quality must be checked by thin-layer chromatography (TLC), and three closely spaced zones in a defined retention factor (Rf) interval specify the saponin reagent. All the Quillaja saponin extracts obtained from different manufacturers and labeled as DAB quality complied with the TLC test. However, the analysis with high-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (HPLC-Q-ToF-MS) clearly showed additionally an intense peak pattern of Madhuca saponins in all measured samples. The TLC test for Mahua seed cake, which is the press residue from Madhuca longifolia, surprisingly showed the same three closely spaced zones in the defined Rf interval. The three zones could be identified as Mi-saponins from Madhuca after scraping and extracting them from the stationary phase of the TLC plate and subsequent measurement by HPLC-Q-ToF-MS. Therefore, the specification of the saponin reagent in DAB characterizes erroneously Madhuca saponins that are not listed as a saponin plant source for the saponin reagent.

Quantitative analysis of human brain microdialysate for target site pharmacokinetics of major anesthetics ketamine, midazolam and propofol.

Brain microdialysis samples of intensive care patients treated with the essential anesthetics ketamine, midazolam and propofol were investigated. Importantly, despite decades of clinical use, comprehensive human cerebral pharmacokinetic data of these drugs is still missing. To encounter this apparent lack of knowledge, we combined cerebral microdialysis with leading-edge analytical instrumentation to monitor the neurochemistry of living human patients. For the quantitative analysis, high performing analytical approaches were developed that can handle minute sample volumes and possible ultralow target analyte levels. The developed methods provided detection limits below 100 ng L-1 for all target analytes and high precision (below 4% RSD intraday). Methods were linear between LODs and 100 µg L-1 for ketamine, 75 µg L-1 for midazolam and 10 µg L-1 for propofol respectively, with coefficients of determination R2≥ 0.999. Further, being aware of the error-prone and demanding translation of microdialysis levels to interstitial concentrations, in vitro approaches for recovery testing of microdialysis probes as well as internal normalization approaches were conducted. Thus, we herein report the first cerebral pharmacokinetic data of ketamine, midazolam and propofol determined in microdialysis samples of 15 neurointensive care patients. We could prove blood-brain barrier penetration of all of the investigated anesthetics and could correlate applied dosages and actual brain exposition of ketamine. However, we emphasize the need of an expanded prospective study including individual microdialysis recovery testing as well as matched serum and/or cerebrospinal fluid collection for a more comprehensive cerebral pharmacokinetic understanding.

Differentiation of Polyamide 6, 6.6, and 12 Contaminations in Polyolefin-Recyclates Using HPLC Coupled to Drift-Tube Ion-Mobility Quadrupole Time-of-Flight Mass Spectrometry.

Recycling is a current hot topic with a focus especially on plastics. The quality of such plastic recyclates is of utmost importance for further processing because impurities lead to a reduction thereof. Contaminations originating from other polymers are highly problematic due to their immiscibility with the recyclate, leading to possible product failures. Therefore, methods for the determination of polymer impurities in recyclates should be investigated. In this paper, an approach for the identification of three different polyamide grades (polyamide 6, 6.6, and 12) is presented, applicable for the analysis of polyolefin-recyclates. An HPLC equipped with a drift-tube ion-mobility QTOF-MS was used for the identification and differentiation of compounds originating from the polyamides, which were then used as markers. These marker compounds are specific for each type and can be identified by their corresponding value of the collision cross section (CCS). After a simple sample preparation, all three types of polyamides were identified within one measurement. In particular, the problematic differentiation of polyamide 6 and 6.6 was easily made possible.

Uptake and bio-transformation of telmisartan by cress (Lepidium sativum) from sewage treatment plant effluents using high-performance liquid chromatography/drift-tube ion-mobility quadrupole time-of-flight mass spectrometry.

In the present study, the uptake and metabolization of the sartan drug telmisartan by a series of plants was investigated. Thereby for seven potential metabolites, modifications on the telmisartan molecule such as hydroxylation and/or glycosylation could be tentatively identified. For two additional signals detected at accurate masses m/z 777.3107 and m/z 793.3096, no suggestions for molecular formulas could be made. Further investigations employing garden cress (Lepidium sativum) as a model plant were conducted. This was done in order to develop an analytical method allowing the detection of these substances also under environmentally relevant conditions. For this reason, the knowledge achieved from treatment of the plants with rather high concentrations of the parent drug (10 mg L-1) was compared with results obtained when using solutions containing telmisartan in the µg - ng L-1 range. Thereby the parent drug and up to three tentative drug-related metabolites could still be detected. Finally cress was cultivated in water taken from a local waste water treatment plant effluent containing 90 ng L-1 of telmisartan and harvested and the cress roots were extracted. In this extract, next to the parent drug one major metabolite, namely telmisartan-glucose could be identified.

Time study on the uptake of four different beta-blockers in garden cress (Lepidium sativum) as a model plant.

The aim of this study was to investigate the uptake of four beta-blockers by the model plant Lepidium sativum (garden cress) and their possible metabolization over a time period of 8 days. Therefore, cress was grown hydroponically in tap water for a week until they were matured, following irrigation with drug-containing water over the course of another 8 days. Samples were taken at days 1, 2, 4, and 8 after irrigation started. All four beta-blockers were taken up by the plants and the different octanol-water coefficients (log P) of the drugs have an influence on the uptake speed in the roots of the plants. The log P seems to have no influence on the translocation of the drugs from the root to the shoots. Furthermore, neither phase I nor phase II metabolization occurred inside the plants.

Development of an LC-MS method for the semiquantitative determination of polyamide 6 contaminations in polyolefin recyclates.

Recycling will be of increasing importance in the future, especially for plastic packaging waste mainly consisting of polyolefins. One major problem of recyclates comprises impurities which can have a significant negative impact on future product properties. Polyamide 6 can be found widely as contaminant in recycled polyolefins, leading to a need of quantification methods thereof. In this paper, a method development for the quantitative analysis of polyamide 6 is presented based on analysing ε-caprolactam and related cyclic oligomers as marker compounds in model recyclates of high- and low-density polyethylene and polypropylene compounded with low amounts of polyamide 6. For the method development and tentative identification of the different cyclic compounds, a HPLC-QTOF-MS was used and it was possible to detect six different compounds, ε-caprolactam and the corresponding cyclic di- to hexamer. The quantification was performed with a HPLC-QQQ-MS, equipped with a HILIC column, after sample preparation via microwave-assisted extraction. It could be shown that a good linearity from 0.2 up to 5 wt% polyamide 6 in the different polyolefins can be achieved. The cyclic trimer and tetramer show a low limit of quantification and are therefore well-suited for the quantification, whereas the other cyclic compounds can be then used as qualifiers to avoid false positives. To guarantee the applicability of the method, six real recyclate materials were analysed, whereby in three of them low amounts of polyamide 6 could be detected. Graphical abstract.

A fast-screening approach for the tentative identification of drug-related metabolites from three non-steroidal anti-inflammatory drugs in hydroponically grown edible plants by HPLC-drift-tube-ion-mobility quadrupole time-of-flight mass spectrometry.

The (tentative) identification of unknown drug-related phase II metabolites in plants upon drug uptake remains a challenging task despite improved analytical instrument performance. To broaden the knowledge of possible drug metabolization, a fast-screening approach for the tentative identification of drug-related phase II metabolites is presented in this work. Therefore, an in silico database for the three non-steroidal anti-inflammatory drugs (ketoprofen, mefenamic acid, and naproxen) and a sub-group of their theoretical phase II metabolites (based on combinations with glucose, glucuronic acid, and malonic acid) was created. Next, the theoretical exact masses (protonated species and ammonia adducts) were calculated and used as precursor ions in an autoMS/MS measurement method. The applicability of this workflow was tested on the example of eleven edible plants, which were hydroponically grown in solutions containing the respective drug at a concentration level of 20 mg/L. For the three drugs investigated this led to the tentative identification of 41 metabolites (some of them so far not described in this context), such as combinations of hydroxylated mefenamic acid with up to four glucose units or hydroxylated mefenamic acid with two glucose and three malonic acid units.

Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma.

Targeting oncogenic fusion-genes in pediatric high-grade gliomas (pHGG) with entrectinib has emerged as a highly promising therapeutic approach. Despite ongoing clinical studies, to date, no reports on the treatment of cerebrospinal fluid (CSF) disseminated fusion-positive pHGG exist. Moreover, clinically important information of combination with other treatment modalities such as intrathecal therapy, radiotherapy and other targeted agents is missing. We report on our clinical experience of entrectinib therapy in two CSF disseminated ROS1/NTRK-fusion-positive pHGG cases. Combination of entrectinib with radiotherapy or intrathecal chemotherapy appears to be safe and has the potential to act synergistically with entrectinib treatment. In addition, we demonstrate CSF penetrance of entrectinib for the first time in patient samples suggesting target engagement even upon CSF dissemination. Moreover, in vitro analyses of two novel cell models derived from one case with NTRK-fusion revealed that combination therapy with either a MEK (trametinib) or a CDK4/6 (abemaciclib) inhibitor synergistically enhances entrectinib anticancer effects. In summary, our comprehensive study, including clinical experience, CSF penetrance and in vitro data on entrectinib therapy of NTRK/ROS1-fusion-positive pHGG, provides essential clinical and preclinical insights into the multimodal treatment of these highly aggressive tumors. Our data suggest that combined inhibition of NTRK/ROS1 and other therapeutic vulnerabilities enhances the antitumor effect, which should be followed-up in further preclinical and clinical studies.

HPLC-MS/MS Shows That the Cellular Uptake of All-Trans-Retinoic Acid under Hypoxia Is Downregulated by the Novel Active Agent 5-Methoxyleoligin.

All-trans-retinoic acid (atRA) is the essential derivative of vitamin A and is of interest due to its various biological key functions. As shown in the recent literature, atRA also plays a role in the failing heart during myocardial infarction, the leading cause of death globally. To date insufficient mechanistic information has been available on related hypoxia-induced cell damage and reperfusion injuries. However, it has been demonstrated that a reduction in cellular atRA uptake abrogates hypoxia-mediated cell and tissue damage, which may offer a new route for intervention. Consequently, in this study, the effect of the novel cardio-protective compound 5-methoxyleoligin (5ML) on cellular atRA uptake was tested in human umbilical-vein endothelial cells (HUVECs). For this purpose, a high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method was developed to assess intra-cellular levels of the active substance and corresponding levels of vitamin A and its derivatives, including potential cis/trans isomers. This work also focused on light-induced isomerization and the stability of biological sample material to ensure sample integrity and avoid biased conclusions. This study provides evidence of the inhibitory effect of 5ML on cellular atRA uptake, a promising step toward a novel therapy for myocardial infarction.

Evaluation and optimization of common lipid extraction methods in cerebrospinal fluid samples.

A typical lipidomics approach aims at the simultaneous analysis of a multitude of lipid species from different lipid classes with highest possible sensitivity for all target lipids. Efficient extraction of lipids from the biological matrix is a crucial step in the analytical workflow. Whereas numerous applications of classical and more recently published extraction methods have been reported for blood serum or plasma samples, very little is known about the applicability of these methods for cerebrospinal fluid (CSF). CSF though represents a highly interesting biofluid for the investigation of neurological disorders, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or brain cancer. Since CSF comprises substantially lower endogenous lipid concentrations compared to serum or plasma, the use of highly efficient extraction methods is of utmost importance. In addition, literature on lipid extraction methods is often inconsistent in terms of methodological parameters like temperature, mixing times, or the number of repeated extraction cycles. In this study, four liquid-liquid extraction methods (Folch, Bligh & Dyer, MTBE and BUME) and one protein precipitation method (MMC method) were evaluated using a pooled CSF sample, followed by the investigation of key process parameters (temperature and mixing times) and modifications of the most promising methods, in order to achieve a broad coverage of lipid classes as well as high recoveries and repeatabilities. A modified Folch method turned out as most suitable for the efficient extraction of a broad range of lipid classes from CSF including glycerophospholipids, glycerolipids and sphingolipids. In addition, using cooled solvents and equipment was shown to significantly improve lipid extraction efficiencies. Mixing times should be thoroughly optimized for the lipid classes of interest in order to achieve high recoveries without lipid degradation due to unnecessarily long mixing. Finally, acidification led to improved extraction efficiency for acidic glycerophospholipids.

Analysis of major bile acids in saliva samples of patients with Barrett's esophagus using high-performance liquid chromatography-electrospray ionization-mass spectrometry.

A fast, non-invasive, high-performance liquid chromatographic screening method with electrospray ionization mass spectrometric detection was developed for the analysis of three major glycine-conjugated bile acids in human saliva. Using a mobile phase composed of 80% methanol and 0.1% formic acid, glycocholic, glycodeoxycholic, and glycochenodeoxycholic acids were separated in less than 4 minutes with sensitivity in the low nM range. Bile acids are thought to contribute to the pathology of various complications in gastroesophageal reflux disease, for instance, Barrett's esophagus, which may eventually lead to esophageal carcinoma. In this pilot study, samples of saliva obtained from 15 patients with Barrett's esophagus of various severities were compared to saliva samples from 10 healthy volunteers. Glycochenodeoxycholic acid was significantly elevated in the patients and principal component analysis of all bile acids could distinguish the most severe Barrett's esophagus patients. We also reported on the detection of glycochenodeoxycholic acid in exhaled breath condensate for the first time. The promising results of this pilot study warrant future investigation, aiming at non-invasive diagnostics of Barrett's esophagus susceptibility in patients with gastroesophageal reflux disease.

Cerebrospinal fluid penetration of targeted therapeutics in pediatric brain tumor patients.

Treatment with small-molecule inhibitors, guided by precision medicine has improved patient outcomes in multiple cancer types. However, these compounds are often not effective against central nervous system (CNS) tumors. The failure of precision medicine approaches for CNS tumors is frequently attributed to the inability of these compounds to cross the blood-brain barrier (BBB), which impedes intratumoral target engagement. This is complicated by the fact that information on CNS penetration in CNS-tumor patients is still very limited. Herein, we evaluated cerebrospinal fluid (CSF) drug penetration, a well-established surrogate for CNS-penetration, in pediatric brain tumor patients. We analyzed 7 different oral anti-cancer drugs and their metabolites by high performance liquid chromatography mass spectrometry (HPLC-MS) in 42 CSF samples obtained via Ommaya reservoirs of 9 different patients. Moreover, we related the resulting data to commonly applied predictors of BBB-penetration including ABCB1 substrate-character, physicochemical properties and in silico algorithms. First, the measured CSF drug concentrations depicted good intra- and interpatient precision. Interestingly, ribociclib, vorinostat and imatinib showed high (> 10 nM), regorafenib and dasatinib moderate (1-10 nM) penetrance. In contrast, panobinostat und nintedanib were not detected. In addition, we identified active metabolites of imatinib and ribociclib. Comparison to well-established BBB-penetrance predictors confirmed low molecular weight, high proportion of free-drug and low ABCB1-mediated efflux as central factors. However, evaluation of diverse in silico algorithms showed poor correlation within our dataset. In summary, our study proves the feasibility of measuring CSF concentration via Ommaya reservoirs thus setting the ground for utilization of this method in future clinical trials. Moreover, we demonstrate CNS presence of certain small-molecule inhibitors and even active metabolites in CSF of CNS-tumor patients and provide a potential guidance for physicochemical and biological factors favoring CNS-penetration.