@article{GernerAghaiTrommeschlaegerKrausetal.2022,
  author    = {Gerner, Bettina and Aghai-Trommeschlaeger, Fatemeh and Kraus, Sabrina and Grigoleit, G{\"o}tz Ulrich and Zimmermann, Sebastian and Kurlbaum, Max and Klinker, Hartwig and Isberner, Nora and Scherf-Clavel, Oliver},
  title     = {A physiologically-based pharmacokinetic model of ruxolitinib and posaconazole to predict CYP3A4-mediated drug-drug interaction frequently observed in graft versus host disease patients},
  series = {Pharmaceutics},
  volume    = {14},
  journal   = {Pharmaceutics},
  number    = {12},
  issn      = {1999-4923},
  doi       = {10.3390/pharmaceutics14122556},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297261},
  year      = {2022},
  abstract  = {Ruxolitinib (RUX) is approved for the treatment of steroid-refractory acute and chronic graft versus host disease (GvHD). It is predominantly metabolized via cytochrome P450 (CYP) 3A4. As patients with GvHD have an increased risk of invasive fungal infections, RUX is frequently combined with posaconazole (POS), a strong CYP3A4 inhibitor. Knowledge of RUX exposure under concomitant POS treatment is scarce and recommendations on dose modifications are inconsistent. A physiologically based pharmacokinetic (PBPK) model was developed to investigate the drug-drug interaction (DDI) between POS and RUX. The predicted RUX exposure was compared to observed concentrations in patients with GvHD in the clinical routine. PBPK models for RUX and POS were independently set up using PK-Sim\(^®\) Version 11. Plasma concentration-time profiles were described successfully and all predicted area under the curve (AUC) values were within 2-fold of the observed values. The increase in RUX exposure was predicted with a DDI ratio of 1.21 (C\(_{max}\)) and 1.59 (AUC). Standard dosing in patients with GvHD led to higher RUX exposure than expected, suggesting further dose reduction if combined with POS. The developed model can serve as a starting point for further simulations of the implemented DDI and can be extended to further perpetrators of CYP-mediated PK-DDIs or disease-specific physiological changes.},
  language  = {en}
}
@article{BalonovKurlbaumKoschkeretal.2023,
  author    = {Balonov, Ilja and Kurlbaum, Max and Koschker, Ann-Cathrin and Stier, Christine and Fassnacht, Martin and Dischinger, Ulrich},
  title     = {Changes in plasma metabolomic profile following bariatric surgery, lifestyle intervention or diet restriction — insights from human and rat studies},
  series = {International Journal of Molecular Sciences},
  volume    = {24},
  journal   = {International Journal of Molecular Sciences},
  number    = {3},
  issn      = {1422-0067},
  doi       = {10.3390/ijms24032354},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304462},
  year      = {2023},
  abstract  = {Although bariatric surgery is known to change the metabolome, it is unclear if this is specific for the intervention or a consequence of the induced bodyweight loss. As the weight loss after Roux-en-Y Gastric Bypass (RYGB) can hardly be mimicked with an evenly effective diet in humans, translational research efforts might be helpful. A group of 188 plasma metabolites of 46 patients from the randomized controlled W{\"u}rzburg Adipositas Study (WAS) and from RYGB-treated rats (n = 6) as well as body-weight-matched controls (n = 7) were measured using liquid chromatography tandem mass spectrometry. WAS participants were randomized into intensive lifestyle modification (LS, n = 24) or RYGB (OP, n = 22). In patients in the WAS cohort, only bariatric surgery achieved a sustained weight loss (BMI -34.3\% (OP) vs. -1.2\% (LS), p ≤ 0.01). An explicit shift in the metabolomic profile was found in 57 metabolites in the human cohort and in 62 metabolites in the rodent model. Significantly higher levels of sphingolipids and lecithins were detected in both surgical groups but not in the conservatively treated human and animal groups. RYGB leads to a characteristic metabolomic profile, which differs distinctly from that following non-surgical intervention. Analysis of the human and rat data revealed that RYGB induces specific changes in the metabolome independent of weight loss.},
  language  = {en}
}
@article{AghaiZimmermannKurlbaumetal.2021,
  author    = {Aghai, Fatemeh and Zimmermann, Sebastian and Kurlbaum, Max and Jung, Pius and Pelzer, Theo and Klinker, Hartwig and Isberner, Nora and Scherf-Clavel, Oliver},
  title     = {Development and validation of a sensitive liquid chromatography tandem mass spectrometry assay for the simultaneous determination of ten kinase inhibitors in human serum and plasma},
  series = {Analytical and Bioanalytical Chemistry},
  volume    = {413},
  journal   = {Analytical and Bioanalytical Chemistry},
  issn      = {1618-2642},
  doi       = {10.1007/s00216-020-03031-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231925},
  pages     = {599-612},
  year      = {2021},
  abstract  = {A liquid chromatography tandem mass spectrometry method for the analysis of ten kinase inhibitors (afatinib, axitinib, bosutinib,cabozantinib, dabrafenib, lenvatinib, nilotinib, osimertinib, ruxolitinib, and trametinib) in human serum and plasma for theapplication in daily clinical routine has been developed and validated according to the US Food and Drug Administration andEuropean Medicines Agency validation guidelines for bioanalytical methods. After protein precipitation of plasma samples withacetonitrile, chromatographic separation was performed at ambient temperature using a Waters XBridge® Phenyl 3.5μm(2.1×50 mm) column. The mobile phases consisted of water-methanol (9:1, v/v) with 10 mM ammonium bicarbonate as phase A andmethanol-water (9:1, v/v) with 10 mM ammonium bicarbonate as phase B. Gradient elution was applied at a flow rate of 400μL/min. Analytes were detected and quantified using multiple reaction monitoring in electrospray ionization positive mode. Stableisotopically labeled compounds of each kinase inhibitor were used as internal standards. The acquisition time was 7.0 min perrun. All analytes and internal standards eluted within 3.0 min. The calibration curves were linear over the range of 2-500 ng/mLfor afatinib, axitinib, bosutinib, lenvatinib, ruxolitinib, and trametinib, and 6-1500 ng/mL for cabozantinib, dabrafenib, nilotinib,and osimertinib (coefficients of correlation≥0.99). Validation assays for accuracy and precision, matrix effect, recovery,carryover, and stability were appropriate according to regulatory agencies. The rapid and sensitive assay ensures high throughputand was successfully applied to monitor concentrations of kinase inhibitors in patients.},
  language  = {en}
}
@article{HoeggerKurlbaumMuelek2013,
  author    = {H{\"o}gger, Petra and Kurlbaum, Max and M{\"u}lek, Melanie},
  title     = {Facilitated Uptake of a Bioactive Metabolite of Maritime Pine Bark Extract (Pycnogenol) into Human Erythrocytes},
  series = {PLoS ONE},
  journal   = {PLoS ONE},
  doi       = {10.1371/journal.pone.0063197},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96656},
  year      = {2013},
  abstract  = {Many plant secondary metabolites exhibit some degree of biological activity in humans. It is a common observation that individual plant-derived compounds in vivo are present in the nanomolar concentration range at which they usually fail to display measurable activity in vitro. While it is debatable that compounds detected in plasma are not the key effectors of bioactivity, an alternative hypothesis may take into consideration that measurable concentrations also reside in compartments other than plasma. We analysed the binding of constituents and the metabolite δ-(3,4-dihydroxy-phenyl)-γ-valerolactone (M1), that had been previously detected in plasma samples of human consumers of pine bark extract Pycnogenol, to human erythrocytes. We found that caffeic acid, taxifolin, and ferulic acid passively bind to red blood cells, but only the bioactive metabolite M1 revealed pronounced accumulation. The partitioning of M1 into erythrocytes was significantly diminished at higher concentrations of M1 and in the presence of glucose, suggesting a facilitated transport of M1 via GLUT-1 transporter. This concept was further supported by structural similarities between the natural substrate α-D-glucose and the S-isomer of M1. After cellular uptake, M1 underwent further metabolism by conjugation with glutathione. We present strong indication for a transporter-mediated accumulation of a flavonoid metabolite in human erythrocytes and subsequent formation of a novel glutathione adduct. The physiologic role of the adduct remains to be elucidated.},
  language  = {en}
}
@article{IsbernerGesierichBalakirouchenaneetal.2022,
  author    = {Isberner, Nora and Gesierich, Anja and Balakirouchenane, David and Schilling, Bastian and Aghai-Trommeschlaeger, Fatemeh and Zimmermann, Sebastian and Kurlbaum, Max and Puszkiel, Alicja and Blanchet, Benoit and Klinker, Hartwig and Scherf-Clavel, Oliver},
  title     = {Monitoring of dabrafenib and trametinib in serum and self-sampled capillary blood in patients with BRAFV600-mutant melanoma},
  series = {Cancers},
  volume    = {14},
  journal   = {Cancers},
  number    = {19},
  issn      = {2072-6694},
  doi       = {10.3390/cancers14194566},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288109},
  year      = {2022},
  abstract  = {Simple Summary In melanoma patients treated with dabrafenib and trametinib, dose reductions and treatment discontinuations related to adverse events (AE) occur frequently. However, the associations between patient characteristics, AE, and exposure are unclear. Our prospective study analyzed serum (hydroxy-)dabrafenib and trametinib exposure and investigated its association with toxicity and patient characteristics. Additionally, the feasibility of at-home sampling of capillary blood was assessed, and a model to convert capillary blood concentrations to serum concentrations was developed. (Hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or AE. Co-medication with P-glycoprotein inducers was associated with lower trough concentrations of trametinib but not (hydroxy-)dabrafenib. The applicability of the self-sampling of capillary blood was demonstrated. Our conversion model was adequate for estimating serum exposure from micro-samples. The monitoring of dabrafenib and trametinib may be useful for dose modification and can be optimized by at-home sampling and our new conversion model. Abstract Patients treated with dabrafenib and trametinib for BRAF\(^{V600}\)-mutant melanoma often experience dose reductions and treatment discontinuations. Current knowledge about the associations between patient characteristics, adverse events (AE), and exposure is inconclusive. Our study included 27 patients (including 18 patients for micro-sampling). Dabrafenib and trametinib exposure was prospectively analyzed, and the relevant patient characteristics and AE were reported. Their association with the observed concentrations and Bayesian estimates of the pharmacokinetic (PK) parameters of (hydroxy-)dabrafenib and trametinib were investigated. Further, the feasibility of at-home sampling of capillary blood was assessed. A population pharmacokinetic (popPK) model-informed conversion model was developed to derive serum PK parameters from self-sampled capillary blood. Results showed that (hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or toxicity. Co-medication with P-glycoprotein inducers was associated with significantly lower trough concentrations of trametinib (p = 0.027) but not (hydroxy-)dabrafenib. Self-sampling of capillary blood was feasible for use in routine care. Our conversion model was adequate for estimating serum PK parameters from micro-samples. Findings do not support a general recommendation for monitoring dabrafenib and trametinib but suggest that monitoring can facilitate making decisions about dosage adjustments. To this end, micro-sampling and the newly developed conversion model may be useful for estimating precise PK parameters.},
  language  = {en}
}
@article{SchraderRieseKurlbaumetal.2021,
  author    = {Schrader, Nikolas and Riese, Thorsten and Kurlbaum, Max and Meybohm, Patrick and Kredel, Markus and Surat, G{\"u}zin and Scherf-Clavel, Oliver and Strate, Alexander and Pospiech, Andreas and Hoppe, Kerstin},
  title     = {Personalized antibiotic therapy for the critically ill: Implementation strategies and effects on clinical outcome of piperacillin therapeutic drug monitoring — a descriptive retrospective analysis},
  series = {Antibiotics},
  volume    = {10},
  journal   = {Antibiotics},
  number    = {12},
  issn      = {2079-6382},
  doi       = {10.3390/antibiotics10121452},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250052},
  year      = {2021},
  abstract  = {Therapeutic drug monitoring (TDM) is increasingly relevant for an individualized antibiotic therapy and subsequently a necessary tool to reduce multidrug-resistant pathogens, especially in light of diminishing antimicrobial capabilities. Critical illness is associated with profound pharmacokinetic and pharmacodynamic alterations, which challenge dose finding and the application of particularly hydrophilic drugs such as β-lactam antibiotics. Methods: Implementation strategy, potential benefit, and practicability of the developed standard operating procedures were retrospectively analyzed from January to December 2020. Furthermore, the efficacy of the proposed dosing target of piperacillin in critically ill patients was evaluated. Results: In total, 160 patients received piperacillin/tazobactam therapy and were subsequently included in the study. Of them, 114 patients received piperacillin/tazobactam by continuous infusion and had at least one measurement of piperacillin serum level according to the standard operating procedure. In total, 271 measurements were performed with an average level of 79.0 ± 46.0 mg/L. Seventy-one piperacillin levels exceeded 100 mg/L and six levels were lower than 22.5 mg/L. The high-level and the low-level group differed significantly in infection laboratory parameters (CRP (mg/dL) 20.18 ± 11.71 vs. 5.75 ± 5.33) and renal function [glomerular filtration rate (mL/min/1.75 m2) 40.85 ± 26.74 vs. 120.50 ± 70.48]. Conclusions: Piperacillin levels are unpredictable in critically ill patients. TDM during piperacillin/tazobactam therapy is highly recommended for all patients. Although our implementation strategy was effective, further strategies implemented into the daily clinical workflow might support the health care staff and increase the clinicians' alertness.},
  language  = {en}
}
@article{MaerzKurlbaumRocheLancasteretal.2021,
  author    = {M{\"a}rz, Juliane and Kurlbaum, Max and Roche-Lancaster, Oisin and Deutschbein, Timo and Peitzsch, Mirko and Prehn, Cornelia and Weismann, Dirk and Robledo, Mercedes and Adamski, Jerzy and Fassnacht, Martin and Kunz, Meik and Kroiss, Matthias},
  title     = {Plasma Metabolome Profiling for the Diagnosis of Catecholamine Producing Tumors},
  series = {Frontiers in Endocrinology},
  volume    = {12},
  journal   = {Frontiers in Endocrinology},
  issn      = {1664-2392},
  doi       = {10.3389/fendo.2021.722656},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245710},
  year      = {2021},
  abstract  = {Context Pheochromocytomas and paragangliomas (PPGL) cause catecholamine excess leading to a characteristic clinical phenotype. Intra-individual changes at metabolome level have been described after surgical PPGL removal. The value of metabolomics for the diagnosis of PPGL has not been studied yet. Objective Evaluation of quantitative metabolomics as a diagnostic tool for PPGL. Design Targeted metabolomics by liquid chromatography-tandem mass spectrometry of plasma specimens and statistical modeling using ML-based feature selection approaches in a clinically well characterized cohort study. Patients Prospectively enrolled patients (n=36, 17 female) from the Prospective Monoamine-producing Tumor Study (PMT) with hormonally active PPGL and 36 matched controls in whom PPGL was rigorously excluded. Results Among 188 measured metabolites, only without considering false discovery rate, 4 exhibited statistically significant differences between patients with PPGL and controls (histidine p=0.004, threonine p=0.008, lyso PC a C28:0 p=0.044, sum of hexoses p=0.018). Weak, but significant correlations for histidine, threonine and lyso PC a C28:0 with total urine catecholamine levels were identified. Only the sum of hexoses (reflecting glucose) showed significant correlations with plasma metanephrines. By using ML-based feature selection approaches, we identified diagnostic signatures which all exhibited low accuracy and sensitivity. The best predictive value (sensitivity 87.5\%, accuracy 67.3\%) was obtained by using Gradient Boosting Machine Modelling. Conclusions The diabetogenic effect of catecholamine excess dominates the plasma metabolome in PPGL patients. While curative surgery for PPGL led to normalization of catecholamine-induced alterations of metabolomics in individual patients, plasma metabolomics are not useful for diagnostic purposes, most likely due to inter-individual variability.},
  language  = {en}
}
@article{IsbernerKrausGrigoleitetal.2021,
  author    = {Isberner, Nora and Kraus, Sabrina and Grigoleit, G{\"o}tz Ulrich and Aghai, Fatemeh and Kurlbaum, Max and Zimmermann, Sebastian and Klinker, Hartwig and Scherf-Clavel, Oliver},
  title     = {Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice-a prospective single-center trial},
  series = {Cancer Chemotherapy and Pharmacology},
  volume    = {88},
  journal   = {Cancer Chemotherapy and Pharmacology},
  number    = {6},
  issn      = {1432-0843},
  doi       = {10.1007/s00280-021-04351-w},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266476},
  pages     = {973-983},
  year      = {2021},
  abstract  = {Purpose Knowledge on Ruxolitinib exposure in patients with graft versus host disease (GvHD) is scarce. The purpose of this prospective study was to analyze Ruxolitinib concentrations of GvHD patients and to investigate effects of CYP3A4 and CYP2C9 inhibitors and other covariates as well as concentration-dependent effects. Methods 262 blood samples of 29 patients with acute or chronic GvHD who were administered Ruxolitinib during clinical routine were analyzed. A population pharmacokinetic model obtained from myelofibrosis patients was adapted to our population and was used to identify relevant pharmacokinetic properties and covariates on drug exposure. Relationships between Ruxolitinib exposure and adverse events were assessed. Results Median of individual mean trough serum concentrations was 39.9 ng/mL at 10 mg twice daily (IQR 27.1 ng/mL, range 5.6-99.8 ng/mL). Applying a population pharmacokinetic model revealed that concentrations in our cohort were significantly higher compared to myelofibrosis patients receiving the same daily dose (p < 0.001). Increased Ruxolitinib exposure was caused by a significant reduction in Ruxolitinib clearance by approximately 50\%. Additional comedication with at least one strong CYP3A4 or CYP2C9 inhibitor led to a further reduction by 15\% (p < 0.05). No other covariate affected pharmacokinetics significantly. Mean trough concentrations of patients requiring dose reduction related to adverse events were significantly elevated (p < 0.05). Conclusion Ruxolitinib exposure is increased in GvHD patients in comparison to myelofibrosis patients due to reduced clearance and comedication with CYP3A4 or CYP2C9 inhibitors. Elevated Ruxolitinib trough concentrations might be a surrogate for toxicity.},
  language  = {en}
}
@phdthesis{Kurlbaum2011,
  author    = {Kurlbaum, Max},
  title     = {Verteilungsvorg{\"a}nge und Metabolismus ausgew{\"a}hlter Verbindungen eines standardisierten Kiefernrindenextraktes in menschlichem Blut},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-64794},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2011},
  abstract  = {Sekund{\"a}re Pflanzenstoffe zeichnen sich wegen ihrer heterogenen Zusammensetzung und großen Strukturvariabilit{\"a}t durch eine komplexe Pharmakokinetik aus. Wissen um die Pharmakokinetik ist wiederum f{\"u}r die Beurteilung von pharmakodynamischen Prozessen unabdingbar. Ziel dieser Arbeit war es durch die Bestimmung wichtiger pharmakokinetischer Parameter zur Erweiterung des Verst{\"a}ndnisses um die Verteilung von verschiedenen Bestandteilen und Metaboliten eines standardisierten Extraktes der franz{\"o}sischen Meereskieker (pinus pinaster) im menschlichen K{\"o}rper beizutragen. Es erfolgte zun{\"a}chst, unter Verwendung zweier verschiedener Methoden, die Bestimmung der Plasmaproteinbindung dieser Substanzen. Hierbei fand eine affinit{\"a}tschromatographische Methode mit immobilisiertem Albumin Anwendung. Die Flavonoide Taxifolin, (+)-Catechin sowie das Catechindimer Procyanidin B1 zeigten eine, aufgrund der vorliegenden Polyphenolstruktur der Substanzen gut erkl{\"a}rbare ausgepr{\"a}gte Bindung, w{\"a}hrend f{\"u}r Kaffes{\"a}ure, Ferulas{\"a}ure und ein δ-(3,4-Dihydroxyphenyl)-γ-valerolacton (Metabolit M1), das in vivo als Metabolit aus(+)-Catechin gebildet wird, eine wesentlich geringere Affinit{\"a}t zu Albumin ermittelt werden konnte. Desweiteren kam eine Filtrationsmethode zur Anwendung, die durch Abtrennung der Proteine aus dem Plasma eine Bestimmung der Bindung erm{\"o}glichte. Um die in Vorversuchen gezeigte ausgepr{\"a}gte unspezifische Bindung der Flavonoide (+)-Catechin und Taxifolin an Membran- und Gef{\"a}ßoberfl{\"a}chen zu minimieren wurde eine Vorbehandlung der Membranen vorgenommen. Die Resultate beider Methoden zeigten eine gute {\"U}bereinstimmung, ausgenommen der bei der Ultrafiltration erhaltenen geringen Proteinbindung des Procyanidin B1. Auch die Ultrafiltrationsmethode ergab f{\"u}r Taxifolin und (+)-Catechin eine beinahe vollst{\"a}ndige Bindung. F{\"u}r die Phenolcarbons{\"a}uren Ferulas{\"a}ure und Kaffees{\"a}ure sowie den Metaboliten M1 hingegen ergaben sich geringere Affinit{\"a}ten so dass die Ergebnisse der affinit{\"a}tschromatographischen Methode best{\"a}tigt und durch die Verwendung von zwei verschiedenen unabh{\"a}ngigen Bestimmungsans{\"a}tzen eine gesteigerte Aussagekraft der Resultate erreicht werden konnte. Eine weitere Erg{\"a}nzung der Aufkl{\"a}rung des pharmakokinetischen Profils erfolgte durch die Ermittlung der Verteilung dieser Substanzen zwischen Plasma und verschiedenen Blutzellen. Insbesondere f{\"u}r den Metaboliten M1 zeigte sich bei einigen der Versuche eine ausgepr{\"a}gte Affinit{\"a}t zu Erythrozyten und mononukle{\"a}ren Zellen. Ob diesem Ph{\"a}nomen m{\"o}glicherweise aktive Transportmechanismen zu Grunde lagen sollte durch weiterf{\"u}hrende Betrachtungen gekl{\"a}rt werden. Die Untersuchungen ergaben, dass an dieser Verteilung weder ein Aminos{\"a}uretransporter noch das para-Glykoprotein beteiligt gewesen waren, jedoch ließen erg{\"a}nzende Versuche den Schluss zu, dass eine erleichterte Diffusion in das Zellinnere durch den Glucose-Transporter GLUT-1 erm{\"o}glicht werden k{\"o}nnte. Diese Vermutung wurde durch vergleichende Energiefeld-,Oberfl{\"a}chen-, und Volumenberechnungen zwischen dem nat{\"u}rlichen Substrat des Transporters Glucose und dem Metaboliten M1 gest{\"u}tzt. Aufbauend auf den Ergebnissen der Verteilungsversuche wurde ein m{\"o}glicher intrazellul{\"a}rer Metabolismus der Substanzen in Erythrozyten und mononukle{\"a}ren Zellen, insbesondere durch Reaktionen des Phase II Metabolismus, untersucht. Mittels massenspektrometrischer Untersuchungen konnten Hinweise auf die Bildung eines Addukts zwischen Glutathion und dem Metaboliten M1 in Erythrozyten gefunden werden. Abschließend wurde durch die Bestimmung der protektiven Eigenschaften des Metaboliten M1 gegen oxidative Sch{\"a}digungen der Erythrozytenmembran auch ein pharmakodynamischer Aspekt dieser Verbindung hinzugef{\"u}gt. Zwar zeigte sich bereits in einem Konzentrationsbereich von 1 μM eine ausgepr{\"a}gte antioxidative Aktivit{\"a}t des Metaboliten M1, jedoch konnte kein Hinweis auf Beeinflussung oxidativer Membransch{\"a}digungen durch m{\"o}glicherweise intrazellul{\"a}r gebildete Konjugate obiger Verbindung gefunden werden. Im Rahmen dieser Arbeit konnten f{\"u}r verschiedene Bestandteile eines Kiefernrindenextraktes und ein δ-(3,4-Dihydroxyphenyl)-γ-valerolacton Plasmaproteinbindungen und erstmals die Verteilung dieser Substanzen zwischen Plasma und Blutzellen ermittelt werden. Insbesondere die in einigen Versuchen gezeigte Aufnahme bzw. Adsorption k{\"o}nnte einen Beitrag zur Kl{\"a}rung der Beobachtung liefern, dass eine deutliche Diskrepanz gefunden wurde zwischen in vivo gemessenen Plasmakonzentrationen, welche in vitro nicht ausreichend sind um deutliche Effekte auszul{\"o}sen und Ergebnissen aus ex vivo Untersuchungen, die eine deutliche Beeinflussung insbesondere antiinflammatorischer Prozesse zeigten.},
  subject      = {Pharmakokinetik},
  language  = {de}
}