W. Jager - Academia.edu (original) (raw)

Papers by W. Jager

Wiener Medizinische Wochenschrift, 2014

Many endogenous and xenobiotic substances and their metabolites are substrates for drug metaboliz... more Many endogenous and xenobiotic substances and their metabolites are substrates for drug metabolizing enzymes and cellular transporters. These proteins may not only contribute to bioavailability of molecules but also to uptake into organs and, consequently, to overall elimination. The coordinated action of uptake transporters, metabolizing enzymes, and efflux pumps, therefore, is a precondition for detoxification and elimination of drugs. As the understanding of the underlying mechanisms is important to predict alterations in drug disposal, adverse drug reactions and, finally, drug-drug interactions, this review illustrates the interplay between selected uptake/efflux transporters and phase I/II metabolizing enzymes. Keywords P-glycoprotein (ABCB1) • Multidrug resistance protein 2 (ABCC2) • Organic anion transporting polypeptides (SCLOs) • UDP-glucuronosyltransferases (UGTs) • Cytochrome P450s (CYPs) Zusammenspiel von arzneistoffmetabolisierenden Enzymen mit zellulären Transportern Zusammenfassung Viele endogene Substanzen und Xenobiotika und ihre Metaboliten sind Substrate für arzneistoffmetabolisierende Enzyme und zelluläre Transporter. Diese Proteine beeinflussen nicht nur die Bioverfügbarkeit, sondern auch deren Aufnahme in Organe, die Plasmakonzentration sowie die Ausscheidung. Das koordinierte Zusammenspiel von Aufnahmetransportern, arzneistoffmetabolisierenden Enzymen und Effluxpumpen ist eine Voraussetzung für Entgiftung und Ausscheidung von Arzneistoffen. Das Verständnis der zugrundeliegenden Mechanismen ist essentiell, um Elimination, Nebenwirkungen und letztendlich Wechselwirkungen vorherzusagen. Daher soll in dieser Übersichtsarbeit das Zusammenspiel am Beispiel von ausgewählten Aufnahme/Effluxtransportern mit Phase I/II Enzyme veranschaulicht werden. Schlüsselwörter P-Glykoprotein (ABCB1) • Multidrug resistance protein 2 (ABCC2) • Organic anion transporting polypeptides (SCLOs) • UDP-Glucuronosyltransferasen (UGTs) • Cytochrom P450 (CYP)

Phytotherapy Research, 1992

This communication is a warning to potential users of allicin, which is adsorbed on silicate carr... more This communication is a warning to potential users of allicin, which is adsorbed on silicate carriers, to be used either as an analytical standard or as a source of allicin for biological experiments. Preparations of this type are invalid as calibrators, since they do not liberate their allicin content quantitatively and unchanged.

Intensive Care Medicine, 2010

Moxifloxacin penetrates intra-abdominal abscesses and accumulates in the abscess fluid, report re... more Moxifloxacin penetrates intra-abdominal abscesses and accumulates in the abscess fluid, report researchers from Germany. Their open-label trial analysed data from eight patients who had intraabdominal infection and a localised intra-abdominal abscess. The patients received IV moxifloxacin 400mg over 1 hour, starting about 2 hours prior to interventional drainage. One hour after infusion initiation, the geometric mean plasma moxifloxacin concentration was 4.46 µg/mL; the concentration decreased to 0.26 µg/mL 24 hours after administration. Moxifloxacin concentrations in abscess fluid peaked at 1.94 µg/mL 3 hours after administration, then decreased to a geometric mean of 0.43 µg/mL at 24 hours. After 12-24 hours, moxifloxacin abscess fluid concentrations tended to exceed plasma concentrations. The abscess fluid/ plasma concentration ratio continually increased over 24 hours.

European Journal of Cancer, 1997

Bioorganic & Medicinal Chemistry, 2007

Resveratrol ((E)-3,4&amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;,5-trihydroxy-stilbene), a p... more Resveratrol ((E)-3,4&amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;,5-trihydroxy-stilbene), a phytoalexin found in various plants, shows non-selective cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibition. In order to find more selective COX inhibitors a series of bridged stilbene derivatives was synthesized and evaluated for their ability to inhibit both COX-1 and COX-2 in vitro. The compounds showed a high rate of COX-1 inhibition with the most potent compounds exhibiting submicromolar IC(50) values and high selectivity indices. A prediction model for COX-inhibiting activity was also developed using the classical LIE approach resulting in consistent docking data for our molecule sample. Phenyl substituted 1,2-dihydronaphthalene derivatives and 1H-indene derivatives therefore represent a novel class of highly selective COX-1 inhibitors and land promising candidates for in vivo studies.

Archives of Toxicology, 2013

generating "circular chemorepellent-induced defects" (CCIDs) that are reminiscent to the entry ga... more generating "circular chemorepellent-induced defects" (CCIDs) that are reminiscent to the entry gates through which tumour emboli intravasate lymphatics. We found that the ion channel blocker carbamazepine (which is clinically used to treat epilepsy, schizophrenia and other neurological disorders) inhibited CCID formation significantly. This effect correlated with the inhibition of the activities of NF-κB, which contributes to cell motility, and with the inactivation of the mobility proteins MLC2, MYPT1 and FAK which are necessary for LEC migration. NF-κB activity and cell movement are prerequisites of CCID formation. On the other hand, the expression of the motility protein paxillin and of the NF-κB-dependent adhesion mediator ICAM-1 was unchanged. Also the activity of ALOX12 was unaffected. ALOX12 is the main enzyme synthesising 12(S)-HETE, which then triggers CCID formation. The relevance of the inhibition of CYP1A1, which is also involved in the generation of mid-chain HETEs such as 12(S)-HETE, by

Archiv der Pharmazie, 2002

A series of thienothiazines was synthesized and tested for their ability to inhibit Pglycoprotein... more A series of thienothiazines was synthesized and tested for their ability to inhibit Pglycoprotein, which is responsible for multidrug resistance in tumor cells. Highest activity was found for compounds with a homoveratryl side chain, which is also present in other modulators of multidrug resistance, such as verapamil. Although for several classes of MDR-modulators lipophilicity was shown to be a major determinant for high activity, no satisfactory correlation was obtained for the set of thienothiazines (r = 0.35). However, the use of molar refractivity as descriptor yields a good correlation with biological activity.This gives renewed evidence for the importance of molar refractivity and indicates that, in addition to lipophilicity, polar interactions also play an important role in ligand/receptor interaction.

Journal of Antimicrobial Chemotherapy, 2005

Linezolid is a new antibacterial agent with a broad spectrum of activity against Gram-positive pa... more Linezolid is a new antibacterial agent with a broad spectrum of activity against Gram-positive pathogens including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp., and penicillin-resistant Streptococcus pneumoniae. The aim of this prospective, single-centre, open-label, two-arm study was to investigate the pharmacokinetics of linezolid during continuous venovenous haemofiltration (CVVH) in critically ill patients and to derive a dosage recommendation. Patients and methods: Twenty anuric ICU patients undergoing CVVH (mean age and body weight 60.7 ± 10.9 years and 86.0 ± 18.0 kg) were included. All patients received linezolid 600 mg intravenously every 12 h. CVVH was performed using highly permeable polysulphone membranes (PSHF 1200, Baxter, Germany and AV 400, Fresenius, Germany). Mean blood flow rate and ultrafiltration rate were 186 ± 15 and 40 ± 8 mL/min, respectively. Post-dilution was performed. Results: The pharmacokinetics of linezolid in critically ill patients with acute renal failure undergoing CVVH were comparable to healthy subjects and patients without renal impairment. The elimination half-life, total clearance and haemofiltration clearance were 4.3 ± 1.7 h, 9.3 ± 3.5 L/h and 1.9 ± 0.8 L/h, respectively. Conclusions: Our results showed that linezolid was highly removable by CVVH. These data suggest that a schedule of 600 mg linezolid at least twice daily may also be an appropriate dosing for patients with severe Gram-positive infections undergoing CVVH with both types of membranes.

Journal of Nuclear Medicine, 2019

PET with avid substrates of P-glycoprotein (ABCB1) provided evidence of the role of this efflux t... more PET with avid substrates of P-glycoprotein (ABCB1) provided evidence of the role of this efflux transporter in effectively restricting the brain penetration of its substrates across the human blood-brain barrier (BBB). This may not reflect the situation for weak ABCB1 substrates including several antidepressants, antiepileptic drugs, and neuroleptics, which exert central nervous system effects despite being transported by ABCB1. We performed PET with the weak ABCB1 substrate 11 C-metoclopramide in humans to elucidate the impact of ABCB1 function on its brain kinetics. Methods: Ten healthy male subjects underwent 2 consecutive 11 C-metoclopramide PET scans without and with ABCB1 inhibition using cyclosporine A (CsA). Pharmacokinetic modeling was performed to estimate the total volume of distribution (V T) and the influx (K 1) and efflux (k 2) rate constants between plasma and selected brain regions. Furthermore, 11 C-metoclopramide washout from the brain was estimated by determining the elimination slope (k E,brain) of the brain time-activity curves. Results: In baseline scans, 11 C-metoclopramide showed appreciable brain distribution (V T 5 2.11 ± 0.33 mL/cm 3). During CsA infusion, whole-brain gray matter V T and K 1 were increased by 29% ± 17% and 9% ± 12%, respectively. K 2 was decreased by 15% ± 5%, consistent with a decrease in k E,brain (−32% ± 18%). The impact of CsA on outcome parameters was significant and similar across brain regions except for the pituitary gland, which is not protected by the BBB. Conclusion: Our results show for the first time that ABCB1 does not solely account for the "barrier" property of the BBB but also acts as a detoxifying system to limit the overall brain exposure to its substrates at the human blood-brain interface.

Expert Opinion on Drug Metabolism & Toxicology, 2016

Oncology Reports, 2009

Avemar (MSC) is a nontoxic fermented wheat germ extract, which has been shown to significantly im... more Avemar (MSC) is a nontoxic fermented wheat germ extract, which has been shown to significantly improve the survival rate in patients suffering from various malignancies. We investigated its effects in sensitive and 5-FdUrd/Ara-C cross-resistant H9 human lymphoma cells. After 48 and 72 h of incubation, Avemar inhibited the growth of sensitive H9 cells with IC 50 values of 290 and 200 μg/ml, whereas the growth of 5-FdUrd/Ara-C cross-resistant H9 cells was attenuated with IC 50 values of 180 and 145 μg/ml, respectively. Treatment with 300 μg/ml MSC for 48 h caused dosedependent induction of apoptosis in 48% of sensitive H9 cells. In cross-resistant H9 cells, incubation with 200 μg/ml Avemar for 48 h led to 41% of apoptotic tumor cells. Growth arrest of sensitive H9 cells after exposure to various concentrations of MSC occurred mainly in the S phase of the cell cycle, thereby increasing the cell population from 54 to 73% while depleting cells in the G0-G1 phase from 40 to 19%. Growth arrest in cross-resistant H9 cells occurred also mainly in the S phase, increasing the cell population from 45 to 68% while depleting cells in the G0-G1 phase from 45 to 31%. As MSC treatment likely overcomes 5-FdUrd/Ara-C resistance, further investigations to elucidate the exact mechanisms are warranted. We conclude that Avemar exerts a number of beneficial effects which could support conventional chemotherapy of human malignancies.

Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 2010

The aim of our study was the initial characterization of Organic anion transporting polypeptides ... more The aim of our study was the initial characterization of Organic anion transporting polypeptides (SLCO gene superfamily) in zebrafish (Danio rerio) as an important model species in biomedical and ecotoxicological research, using phylogenetic analysis, membrane topology prediction and tissue expression profiling. The phylogenetic tree of Oatp superfamily in vertebrates was constructed in Mega 3.1. Software, membrane topology was predicted using HMMTOP algorithm, while qRT-PCR was used to determine tissue-specific gene expression levels. Phylogenetic analysis revealed that Oatp superfamily in zebrafish consists of five families that include 14 SLCO genes. Eight out of 14 transporters do have orthologs or co-orthologs in other vertebrates, while 6 members are found only in fish lineage. Topology analysis showed that all zebrafish Oatps consist of 12 transmembrane domains (TMD) with the large fifth extracellular loop (LP5). Tissue distribution analysis revealed that the expression patterns of Oatp2a1, Oatp2b1 and Oatp3a1 follow tissue distribution patterns of their mammalian (co)orthologs. Expression pattern of a newly identified Oatp1d1 is similar to mouse Oatp1a4, while other new zebrafish Oatps (Oatp1e1, 1f2) do not resemble any of the mammalian Oatps. In summary, the described comprehensive analysis of Oatp superfamily in fish represents a first step towards research on toxicological relevance of uptake transporters in aquatic organisms.

Biochemical Pharmacology, 1999

ABSTRACT

Alimentary Pharmacology & Therapeutics, 2001

Background:Esomeprazole, the S‐isomer of omeprazole, is the first proton pump inhibitor developed... more Background:Esomeprazole, the S‐isomer of omeprazole, is the first proton pump inhibitor developed as a single isomer for the treatment of acid‐related diseases.Aim:To examine the pharmacokinetics and pharmacodynamics of esomeprazole.Methods:In a crossover study, 12 healthy males received 5, 10 or 20 mg of esomeprazole, or 20 mg of omeprazole, once daily over 5 days. The pharmacokinetics and effects on pentagastrin‐stimulated peak acid output of esomeprazole and omeprazole were studied on days 1 and 5.Results:The area under the curve (AUC) of both esomeprazole and omeprazole increased from day 1 to day 5. The correlation between acid inhibition and AUC for esomeprazole could be well described with a sigmoid Emax model. The mean inhibition values of the pentagastrin‐stimulated peak acid output on day 1 for 5, 10 and 20 mg of esomeprazole were 15%, 29% and 46%, respectively; the corresponding day 5 values were 28%, 62% and 90%. The mean inhibition values of the pentagastrin‐stimulated ...

Frontiers in Molecular Biosciences, 2017

Journal of Pharmacy & Pharmaceutical Sciences, 2015

Purpose. Natural health products (NHPs), including melatonin, are widely used products. Despite t... more Purpose. Natural health products (NHPs), including melatonin, are widely used products. Despite the widespread assumption that all NHPs are safe, they contain pharmacologically active substances and can therefore have adverse effects and/or interact with pharmaceuticals. Objective: To investigate the mechanism underlying NHP interactions identified through the Pharmacy SONAR active surveillance study. Methods: Active surveillance was undertaken in community pharmacies to identify adverse events in patients who had recently taken NHPs together with conventional pharmaceuticals. For suspected NHP-pharmaceutical interactions, the possible mechanism of action was explored by in vitro analysis of samples of different products to identify cytochrome P450 enzyme (CYP) inhibition potential. Results: Active surveillance identified a 19-year-old male taking citalopram, nortriptyline and oxycodone concomitantly and who experienced severe sedation when melatonin was added to this regimen. In vi...

BioMed Research International, 2015

Anticancer research

Resveratrol (RV), a naturally occurring phytoalexin, exerts manifold biological effects against a... more Resveratrol (RV), a naturally occurring phytoalexin, exerts manifold biological effects against a variety of human tumor cell lines. In this study, the cytotoxic and biological effects of novel RV derivatives were investigated in prostate cancer cells. Cytotoxicity of the compounds was assessed by clonogenic assays in PC-3, LNCaP and DU-145 human prostate cancer cell lines. Induction of apoptosis was studied by Hoechst-propidium-iodide double staining. Cell cycle phase distribution of prostate cancer cells was analyzed using flow cytometry. Methoxy- and hydroxy-substituted RV derivatives exerted cytotoxic effects against all three cell lines. The most potent compounds, 3,3',4,4',5,5'-hexahydroxy-stilbene and 3,4,4',5-tetramethoxystilbene, induced apoptosis at concentrations lower than RV and caused cell cycle arrest in the cell lines investigated. Introducing additional hydroxy- and methoxymoieties to the stilbene ring of RV is capable of enhancing its cytotoxic and ...

International Journal of Oncology, 2014

The metabolism of 9-aminocamptothecin (9-AC) was investigated in human and rat liver microsomes. ... more The metabolism of 9-aminocamptothecin (9-AC) was investigated in human and rat liver microsomes. In both species 9-AC was almost exclusively biotransformed to dihydroxy-9-AC (M1) and monohydroxy-9-AC (M2). The enzymatic efficiencies of the formation of M1 and M2 (V max /K m) were 1.7-and 2.7-fold higher in rat than in human liver microsomes indicating species-related differences in 9-AC hydroxylation. Incubation in the presence of human recombinant cytochrome P450 (CYP) enzymes demonstrated that the formation of M1 and M2 is mainly catalyzed by CYP3A4 and only to a minor extent by extrahepatic CYP1A1. The predominant role of CYP3A4 was further supported by a dramatic inhibition of metabolite formation in the presence of the CYP3A4 substrates troleandomycin and ketoconazole. Experiments conducted in isolated perfused rat livers further demonstrated that biliary excretion of 9-AC, M1 and M2 during 60 min of perfusion was pronounced and accounted for 17.7±2.59, 0.05±0.01 and 2.75±0.14% of total 9-AC applied to the liver, respectively. In summary, this study established that CYP3A-dependent hydroxylation is the main metabolic pathway for 9-AC in rat and human liver, which have to be taken into consideration during cancer therapy of patients.

In vivo (Athens, Greece)

The incidence of cancer is rapidly increasing and malignancies have become the number two cause o... more The incidence of cancer is rapidly increasing and malignancies have become the number two cause of deaths in the Western world after cardiovascular diseases. In particular, colon cancer represents one of the most frequent types of malignancy. Chemotherapy is, in addition to surgery and irradiation, still one of the main treatment options against this group of diseases. Here, several chemotherapeutic treatment modalities and anticancer compounds for the treatment of colon cancer are reviewed. In particular, a newer group of heterodinucleoside phosphates (dimers), consisting of two well known antimetabolites (5-FdUrd (5-Fluorodeoxyuridine) and Ara-C (Cytarabine)), are presented. These dimers were evaluated in several studies and might offer an additional option for the treatment of various malignancies, in particular colon carcinomas. The results are summarized in detail, as these dimers might have some significant advantages when compared with conventional regimens; they might be adm...