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Variability in Mass Spectrometry-based Quantification of Clinically Relevant Drug Transporters and Drug Metabolizing Enzymes

Wegler, C. (author), Gaugaz, F.Z. (author), Andersson, T.B. (author), Wiśniewski, J.R. (author), Busch, D. (author), Gröer, C. (author), Oswald, S. (author), Norén, A. (author), Weiss, F. (author), Hammer, H.S. (author), Joos, T.O. (author), Poetz, O. (author), Achour, B. (author), Rostami-Hodjegan, A. (author), van de Steeg, E. (author), Wortelboer, H.M. (author), Artursson, P. (author)

Many different methods are used for mass-spectrometry-based protein quantification in pharmacokinetics and systems pharmacology. It has not been established to what extent the results from these various methods are comparable. Here, we compared six different mass spectrometry-based proteomics methods by measuring the expression of clinically...

article 2017

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Pediatric Microdose Study of [14C]Paracetamol to Study Drug Metabolism Using Accelerated Mass Spectrometry: Proof of Concept

Mooij, M.G. (author), van Duijn, E. (author), Knibbe, C.A.J. (author), Windhorst, A.D. (author), Hendrikse, N.H. (author), Vaes, W.H.J. (author), Spaans, E. (author), Fabriek, B.O. (author), Sandman, H. (author), Grossouw, D. (author), Hanff, L.M. (author), Janssen, P.J.J.M. (author), Koch, B.C.P. (author), Tibboel, D. (author), de Wildt, S.N. (author)

Results: Ten infants (aged 0.1–83.1 months) were included; one was excluded as he vomited shortly after administration. In nine patients, [14C]AAP and metabolites in blood samples were detectable at expected concentrations: median (range) maximum concentration (Cmax) [14C]AAP 1.68 (0.75–4.76) ng/L, [14C]AAP-Glu 0.88 (0.34–1.55) ng/L, and [14C...

article 2014

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Clearance and clearance inhibition of the HIV-1 protease inhibitors ritonavir and saquinavir in sandwich-cultured rat hepatocytes and rat microsomes

Treijtel, N. (author), Eijkeren, J.C.H.v. (author), Nijmeijer, S. (author), van der Greef de - Sandt, I.C.J. (author), Freidig, A.P. (author), TNO Kwaliteit van Leven (author)

The metabolism and active transport of ritonavir and saquinavir were studied using sandwich-cultured rat hepatoyctes and rat liver microsomes. For ritonavir four comparable metabolites were observed in the sandwich-culture and in microsomes. For saquinavir eight metabolites were observed in sandwich-culture and 14 different metabolites in...

article 2009

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Recent methodology in the phytochemical analysis of ginseng

Angelova, N. (author), Kong, H.-W. (author), van de Heijden, R. (author), Yang, S.-Y. (author), Choi, Y.H. (author), Kim, H.K. (author), Wang, M. (author), Hankemeier, T. (author), van der Greef, J. (author), Xu, G. (author), Verpoorte, R. (author), TNO Kwaliteit van Leven (author)

This review summarises the most recent developments in ginseng analysis, in particular the novel approaches in sample pre-treatment and the use of high-performance liquid-chromatography-mass spectrometry. The review also presents novel data on analysing ginseng extracts by nuclear magnetic resonance spectroscopy and high-resolution mass...

article 2008

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Transcriptome analysis provides new insights into liver changes induced in the rat upon dietary administration of the food additives butylated hydroxytoluene, curcumin, propyl gallate and thiabendazole

Stierum, R. (author), Conesa, A. (author), Heijne, W. (author), Ommen, B.v. (author), Junker, K. (author), Scott, M.P. (author), Price, R.J. (author), Meredith, C. (author), Lake, B.G. (author), Groten, J. (author), TNO Kwaliteit van Leven (author), KvL (author)

Transcriptomics was performed to gain insight into mechanisms of food additives butylated hydroxytoluene (BHT), curcumin (CC), propyl gallate (PG), and thiabendazole (TB), additives for which interactions in the liver can not be excluded. Additives were administered in diets for 28 days to Sprague-Dawley rats and cDNA microarray experiments were...

article 2008

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Transdermal administration of radiolabelled [14C]rotigotine by a patch formulation: A mass balance trial

Cawello, W. (author), Wolff, H.M. (author), Meuling, W.J.A. (author), Horstmann, R. (author), Braun, M. (author), TNO Kwaliteit van Leven (author)

Background and objective: The dopamine agonist rotigotine has been formulated in a silicone-based transdermal system for once-daily administration. The objective of the present study was to characterise the mass balance of rotigotine in humans after administration of a single transdermal patch containing radiolabelled [14C]rotigotine and to...

article 2007

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Comparison of coumarin-induced toxicity between sandwich-cultured primary rat hepatocytes and rats in vivo: A toxicogenomics approach

Kienhuis, A.S. (author), Wortelboer, H.M. (author), Hoflack, J.C. (author), Moonen, E.J. (author), Kleinjans, J.C.S. (author), van Ommen, B. (author), van Delft, J.H.M. (author), Stierum, R.H. (author), TNO Kwaliteit van Leven (author)

Sandwich-cultured primary rat hepatocytes are often used as an in vitro model in toxicology and pharmacology. However, loss of liver-specific functions, in particular, the decline of cytochrome P450 (P450) enzyme activity, limits the value of this model for prediction of in vivo toxicity. In this study, we investigated whether a hepatic in vitro...

article 2006

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Criteria to distinguish between natural situations and illegal use of boldenone, boldenone esters and boldione in cattle. 1. Metabolite profiles of boldenone, boldenone esters and boldione in cattle urine

Le Bizec, B. (author), Courant, F. (author), Gaudin, I. (author), Bichon, E. (author), Destrez, B. (author), Schilt, R. (author), Draisci, R. (author), Monteau, F. (author), André, F. (author), TNO Kwaliteit van Leven (author)

Boldenone is an androgenic steroid that improves the growth and food conversion in food producing animals. In most countries worldwide, this anabolic steroid is forbidden for meat production. Until recently, the control of its illegal use was based either on 17β-boldenone or 17α-boldenone (its main metabolite in cattle) identification in edible...

article 2006

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Cost-effectiveness of pharmacogenomics in clinical practice: A case study of thiopurine methyltransferase genotyping in acute lymphoblastic leukemia in Europe

van den Akker-van Marle, M.E. (author), Gurwitz, D. (author), Detmar, S.B. (author), Enzing, C.M. (author), Hopkins, M.M. (author), Gutierrez De Mesa, E. (author), Ibarreta, D. (author), TNO Kwaliteit van Leven (author)

Only a few studies have addressed the cost-effectiveness of pharmacogenetics interventions in healthcare. Lack of health economics data on aspects of pharmacogenetics is perceived as one of the barriers hindering its implementation for improving drug safety. Thus, a recent Institute for Prospective Technological Studies (IPTS) study, entitled ...

article 2006

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Inhibition of multidrug resistance proteins MRP1 and MRP2 by a series of α,β-unsaturated carbonyl compounds

Wortelboer, H.M. (author), Usta, M. (author), van Zanden, J.J. (author), van Bladeren, P.J. (author), Rietjens, I.M.C.M. (author), Cnubben, N.H.P. (author), TNO Kwaliteit van Leven (author)

To study the possible interplay between glutathione metabolism of and MRP inhibition by thiol reactive compounds, the interactions of a series of α,β-unsaturated carbonyl compounds with multidrug resistance proteins 1 and 2 (MRP1/ABCC1 and MRP2/ABCC2) were studied. α,β-Unsaturated carbonyl compounds react with glutathione, and therefore either...

article 2005

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Bromobenzene-induced hepatotoxicity at the transcriptome level

Heijne, W.H.M. (author), Slitt, A.L. (author), van Bladeren, P.J. (author), Groten, J.P. (author), Klaassen, C.D. (author), Stierum, R.H. (author), van Ommen, B. (author), TNO Voeding Centraal Instituut voor Voedingsonderzoek TNO (author)

Rats were exposed to three levels of bromobenzene, sampled at 6, 24, and 48 h, and liver gene expression profiles were determined to identify dose and time-related changes. Expression of many genes changed transiently, and dependent on the dose. Few changes were identified after 6 h, but many genes were differentially expressed after 24 h, while...

article 2004

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Inhibition of zaleplon metabolism by cimetidine in the human liver: In vitro studies with subcellular fractions and precision-cut liver slices

Renwick, A.B. (author), Ball, S.E. (author), Tredger, J.M. (author), Price, R.J. (author), Walters, D.G. (author), Kao, J. (author), Scatina, J.A. (author), Lake, B.G. (author), TNO Voeding (author)

The effect of cimetidine on the metabolism of zaleplon (ZAL) in human liver subcellular fractions and precision-cut liver slices was investigated. 2. ZAL was metabolized to a number of products including 5-oxo-ZAL (M2), which is known to be formed by aldehyde oxidase, N-desethyl-ZAL (DZAL), which is known to be formed by CYP3A forms, and N...

article 2002

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Analytical possibilities for the detection of stanozolol and its metabolites

Poelmans, S. (author), de Wasch, K. (author), de Brabander, H.F. (author), van de Wiele, M. (author), Courtheyn, D. (author), van Ginkel, L.A. (author), Sterk, S.S. (author), Delahaut, Ph. (author), Dubois, M. (author), Schilt, R. (author), Nielen, M. (author), Vercammen, J. (author), Impens, S. (author), Stephany, R. (author), Hamoir, T. (author), Pottie, G. (author), van Poucke, C. (author), van Peteghem, C. (author)

In sports doping, as well in man as in horseracing, stanozolol (Stan) was abused and became the subject of metabolism research. Also in veterinary practice, stanozolol became an important misused anabolic steroid. Like most other anabolic steroids, stanozolol has poor gas chromatographic behavior. It is difficult to detect in urine, because of...

article 2002

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17α-Ethyl-5β-estrane-3α,17β-diol, a biological marker for the abuse of norethandrolone and ethylestrenol in slaughter cattle

van Puymbroeck, M. (author), Kuilman, M.E.M. (author), Maas, R.F.M. (author), Witkamp, R.F. (author), Leyssens, L. (author), van Miert, A.S.J.P.A.M. (author), Hendriks, L. (author), van der Zande, D.J.M. (author), Adriaensens, P. (author), Jacobs, M.-P. (author), Raus, J. (author), Centraal Instituut voor Voedingsonderzoek TNO (author)

The metabolism of the illegal growth promoter ethylestrenol (EES) was evaluated in bovine liver cells and subcellular fractions of bovine liver preparations. Incubations with bovine microsomal preparations revealed that EES is extensively biotransformed into norethandrolone (NE), another illegal growth promoter. Furthermore, incubations of...

article 1999

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Disposition of [14C]γ-cyclodextrin in germ-free and conventional rats

de Bie, A.T.H.J. (author), van Ommen, B. (author), Bär, A. (author), Centraal Instituut voor Voedingsonderzoek TNO (author)

The absorption, disposition, metabolism, and excretion of 14C-labeled γ-cyclodextrin ([14C]γ-CD) was examined in four separate experiments with Wistar rats. In experiment 1, [14C]γ-CD (25 μCi, 600 mg/kg body wt) was administered intravenously to four male and four female conventional rats. In experiment 2, [14C]γ- CD (25 μCi, 1000 mg/kg body wt)...

article 1998

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Hydrogen atom abstraction of 3,5-disubstituted analogues of paracetamol by horseradish peroxidase and cytochrome P450

Bessems, J.G.M. (author), de Groot, M.J. (author), Baede, E.J. (author), te Koppele, J.M. (author), Vermeulen, N.P.E. (author), Centraal Instituut voor Voedingsonderzoek TNO (author)

1. The formation of free radicals during enzyme catalysed oxidation of eight 3,5-disubstituted analogues of paracetamol (PAR) has been studied. A simple peroxidase system as well as cytochrome P450-containing systems were used. Radicals were detected by electron spin resonance (ESR) on incubation of PAR and 3,5-diCH3-, 3,5-diC2H5-, 3,5-ditC4H9-,...

article 1998

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Identification of some important metabolites of boldenone in urine and feces of cattle by gas chromatography-mass spectrometry

Centraal Instituut voor Voedingsonderzoek TNO TNO Voeding (author), van Puymbroeck, M. (author), Kuilman, M.E.M. (author), Maas, R.F.M. (author), Witkamp, R.F. (author), Leyssens, L. (author), van der Zande, D.J.M. (author), Gelan, J. (author), Raus, J. (author)

17alpha-Boldenone (17alpha-BOL) and/or 17beta-boldenone (17beta-BOL) appear occasionally in fecal matter of cattle. In addition to 17alpha-BOL, a whole array of boldenone related substances can be found in the same samples. In vitro experiments with microsomal liver preparations and isolated hepatocytes combined with the excretion profiles found...

article 1998

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In vitro liver models are important tools to monitor the abuse of anabolic steroids in cattle

Centraal Instituut voor Voedingsonderzoek TNO TNO Voeding (author), van Puymbroeck, M. (author), Kuilman, M.E.M. (author), Maas, R.F.M. (author), Witkamp, R.F. (author), Leyssens, T. (author), van der Zande, D.J.M. (author), Gelan, J. (author), Raus, J. (author)

Current veterinary residue analysis mainly focuses on the monitoring of residues of the administered parent compound. However, it is possible that larger amounts of metabolites are excreted and that they can have a prolonged excretion period. In order to unravel specific metabolic steps and to identify possible biological markers, two in vitro...

article 1998

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Comparison of five incubation systems for rat liver slices using functional and viability parameters

Olinga, P. (author), Groen, K. (author), Hof, I.H. (author), de Kanter, R. (author), Koster, H.J. (author), Leeman, W.R. (author), Rutten, A.A.J.J.L. (author), van Twillert, K. (author), Groothuis, G.M.M. (author), Centraal Instituut voor Voedingsonderzoek TNO TNO Voeding (author)

Precision-cut liver slices are presently used for various research objects, e.g. to study metabolism, transport, and toxicity of xenobiotics. Various incubation systems are presently employed, but a systematic comparison between these incubation systems with respect to preservation of slice function has not been performed yet. Therefore, we...

article 1997

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Differences in metabolism and isomerization of all-trans-retinoic acid and 9-cis-retinoic acid between human endothelial cells and hepatocytes

Lansink, M. (author), van Bennekum, A.M. (author), Blaner, W.S. (author), Kooistra, T. (author), TNO Preventie en Gezondheid (author)

Retinoic acid stimulates the expression of tissue-type plasminogen activator (t-PA) in vascular endothelial cells in vitro and enhances t-PA levels in plasma and tissues in vivo. Compared with the in vivo situation, high retinoic acid concentrations are required to induce optimally t-PA expression in vitro. These findings led us to study...

article 1997