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Determinants of postprandial plasma bile acid kinetics in human volunteers

Fiamoncini, J. (author), Yiorkas, A.M. (author), Gedrich, K. (author), Rundle, M. (author), Alsters, S.I. (author), Roeselers, G. (author), van den Broek, T.J. (author), Clavel, T. (author), Lagkouvardos, I. (author), Wopereis, S. (author), Frost, G. (author), van Ommen, B. (author), Blakemore, A.I. (author), Daniel, H. (author)

Bile acids (BA) are signaling molecules with a wide range of biological effects, also identified among the most responsive plasma metabolites in the postprandial state. We here describe this response to different dietary challenges and report on key determinants linked to its interindividual variability. Healthy men and women (n = 72, 62 ± 8 yr,...

article 2017

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Microdosing of a Carbon-14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages

Vlaming, M.L. (author), van Duijn, E. (author), Dillingh, M.R. (author), Brands, R. (author), Windhorst, A.D. (author), Hendrikse, N.H. (author), Bosgra, S. (author), Burggraaf, J. (author), de Koning, M.C. (author), Fidder, A. (author), Mocking, J.A. (author), Sandman, H. (author), de Ligt, R.A. (author), Fabriek, B.O. (author), Pasman, W.J. (author), Seinen, W. (author), Alves, T. (author), Carrondo, M. (author), Peixoto, C. (author), Peeters, P.A. (author), Vaes, W.H. (author)

Preclinical development of new biological entities (NBEs), such as human protein therapeutics, requires considerable expenditure of time and costs. Poor prediction of pharmacokinetics in humans further reduces net efficiency. In this study, we show for the first time that pharmacokinetic data of NBEs in humans can be successfully obtained early...

article 2015

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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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Differential effects of pharmacological liver X receptor activation on hepatic and peripheral insulin sensitivity in lean and ob/ob mice

TNO Kwaliteit van Leven (author), Grefhorst, A. (author), van Dijk, T.H. (author), Hammer, A. (author), van der Sluijs, F.H. (author), Havinga, R. (author), Havekes, L.M. (author), Romijn, J.A. (author), Groot, P.H. (author), Reijngoud, D.J. (author), Kuipers, F. (author)

Liver X receptor (LXR) agonists have been proposed to act as anti-diabetic drugs. However, pharmacological LXR activation leads to severe hepatic steatosis, a condition usually associated with insulin resistance and type 2 diabetes mellitus. To address this apparent contradiction, lean and ob/ob mice were treated with the LXR agonist GW-3965 for...

article 2005

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Human systemic exposure to a [14C]-para-phenylenediamine- containing oxidative hair dye and correlation with in vitro percutaneous absorption in human or pig skin

Hueber-Becker, F. (author), Nohynek, G.J. (author), Meuling, W.J.A. (author), Benech-Kieffer, F. (author), Toutain, H. (author), TNO Voeding (author)

We investigated the absorption of a commercial [14C]-PPD- containing oxidative dark-shade hair dye in human volunteers as well as in vitro using human or pig ear skin. The hair of eight male volunteers was cut to a standard length, dyed, washed, dried, clipped and collected. Hair, washing water, materials used in the study and a 24-h scalp wash...

article 2004

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Modeling the in vitro intrinsic clearance of the slowly metabolized compound tolbutamide determined in sandwich-cultured rat hepatocytes

Treijtel, N. (author), Barendregt, A. (author), Freidig, A.P. (author), Blaauboer, B.J. (author), van Eijkeren, J.C.H. (author), TNO Voeding (author)

An alternative approach is introduced in determining the in vitro intrinsic clearance of slowly metabolized compounds. The long-term sandwich rat hepatocyte culture was exploited, allowing for sufficient substrate depletion to obtain a reliable clearance estimation; in its physiology, it resembles the in vivo liver, thus allowing in vivo...

article 2004

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Dietary 135-fold cholecalciferol supplementation severely disturbs the endochondral ossification in growing dogs

Tryfonidou, M.A. (author), Holl, M.S. (author), Stevenhagen, J.J. (author), Buurman, C.J. (author), Deluca, H.F. (author), Oosterlaken-Dijksterhuis, M.A. (author), van den Brom, W.E. (author), van Leeuwen, J.P.T.M. (author), Hazewinkel, H.A.W. (author), Centraal Instituut voor Voedingsonderzoek TNO TNO Voeding (author)

The effects of excessive non-toxic dietary Vitamin D3 supplementation on Ca homeostasis with specific effects on endochondral ossification and skeletal remodeling were investigated in a group of growing Great Dane dogs supplemented with cholecalciferol (Vitamin D3; HVitD) versus a control group (CVitD) (1350 μg versus 11.4 μg Vitamin D3 per...

article 2003

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Moderate cholecalciferol supplementation depresses intestinal calcium absorption in growing dogs

Tryfonidou, M.A. (author), Stevenhagen, J.J. (author), van den Bemd, G.J.C.M. (author), Oosterlaken-Dijksterhuis, M.A. (author), Deluca, H.F. (author), Mol, J.A. (author), van den Brom, W.E. (author), van Leeuwen, J.P.T.M. (author), Hazewinkel, H.A.W. (author), Centraal Instituut voor Voedingsonderzoek TNO (author)

Hormonal regulation of calcium (Ca) absorption was investigated in a cholecalciferol (vitamin D3)supplemented group (hVitD) vs. a control group (cVitD) of growing Great Danes (100 vs. 12.5 μg vitamin D3/kg diet). Although Ca intakes did not differ, fractional Ca absorption was significantly lower in the hVitD group than in the cVitD group. There...

article 2002

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Biological clearance of TEGDMA in guinea pigs

Reichl, F.X. (author), Durner, J. (author), Kunzelmann, K.H. (author), Hickel, R. (author), Spahl, W. (author), Hume, W.R. (author), Moes, G.W.H (author), Kehe, K. (author), Walther, U. (author), Forth, W. (author)

The excretion of the dental composite component triethylene glycol dimethacrylate (TEGDMA) in feces and urine in vivo and, using the pendular perfusion technique with segments of jejunum and colon, the biliary and enteric excretion in situ were investigated in anesthetized guinea pigs. In the in situ experiments guinea pigs (n=4) received TEGDMA...

article 2001

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Distribution and excretion of TEGDMA in guinea pigs and mice

Reichl, F.X. (author), Durner, J. (author), Hickel, R. (author), Kunzelmann, K.H. (author), Jewett, A. (author), Wang, M.Y. (author), Spahl, W. (author), Kreppel, H. (author), Moes, G.W.H. (author), Kehe, K. (author), Walther, U. (author), Forth, W. (author), Hume, W.R. (author)

The monomer triethyleneglycoldimethacrylate (TEGDMA) is used as a diluent in many resin-based dental materials. It was previously shown in vitro that TEGDMA was released into the adjacent biophase from such materials during the first days after placement. In this study, the uptake, distribution, and excretion of 14C-TEGDMA applied via gastric,...

article 2001

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The role of the low-density lipoprotein receptor-related protein (LRP) in the plasma clearance and liver uptake of recombinant single-chain urokinase-type plasminogen activator in rats

van der Kaaden, M.E. (author), Rijken, D.C. (author), Kruijt, J.K. (author), van Berkel, T.J.C. (author), Kuiper, J. (author), TNO Preventie en Gezondheid (author)

Urokinase-type plasminogen activator (u-PA) is used as a thrombolytic agent in the treatment of acute myocardial infarction. In vitro, recombinant single-chain u-PA (rscu-PA) expressed in E. coli is recognized by the Low-Density Lipoprotein Receptor-related Protein (LRP) on rat parenchymal liver cells. In this study we investigated the role of...

article 1997

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Inhibition of mannose receptor-mediated-clearance of tissue-type plasminogen activator (t-PA) by dextran: A new explanation for its antithrombotic effect

Noorman, F. (author), Barrett-Bergshoeff, M.M. (author), Bekkers, M. (author), Emeis, J.J. (author), Rijken, D.C. (author), Gaubius Instituut TNO (author)

Dextran is used during surgery as a prophylactic agent to prevent deep venous thrombosis. Recently it has been shown that dextran increases t-PA plasma concentrations in patients. As dextran is a potential ligand for the mannose receptor, we studied whether this glucose-polymer would be able to inhibit mannose receptor-mediated clearance of t-PA...

article 1997

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Pharmacokinetics of carboplatin with and without amifostine in patients with solid tumors

Korst, A.E.C. (author), van der Sterre, M.L.T. (author), Eeltink, C.M. (author), Fichtinger-Schepman, A.M.J. (author), Vermorken, J.B. (author), van der Vijgh, W.J.F. (author), Centraal Instituut voor Voedingsonderzoek TNO (author)

We showed previously that amifostine (WR 2721; Ethyol), a protector against carboplatin-induced toxicities, changed the pharmacokinetics of carboplatin in tumor-bearing nude mice. In the present study, the influence of amifostine on the pharmacokinetics of carboplatin was studied in patients when carboplatin was given in combination with three...

article 1997

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The influence of aging on the metabolism of simultaneously administered hexobarbital enantiomers and antipyrine before and after phenobarbital induction in male rats: A longitudinal study

Groen, K. (author), Breimer, D.D. (author), Jansen, E.J. (author), van Bezooijen, C.F.A. (author), Gaubius Instituut TNO (author)

The influence of aging on the metabolism of antipyrine (AP) and hexobarbital enantiomers (R-HB and S-HB) with and without phenobarbital (PB) induction was investigated in a longitudinal study in rats aged 6, 12, 24 and 30 months. The metabolic clearances of AP (Cl(m AP)), R-HB (Cl(m R-HB)) and S-HB (Cl(m S-HB)) were used as indicators for P450...

article 1994

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Thrombolytic properties in a rabbit jugular vein thrombosis model of a tissue-type plasminogen activator mutant lacking the growth factor- and kringle 1-domains

Emeis, J.J. (author), Verheijen, J.H. (author), Instituut voor Verouderings- en Vaatziekten Onderzoek TNO (author)

Chemicals/CAS: Recombinant Proteins; Tissue Plasminogen Activator, EC 3.4.21.68

article 1992

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In vivo and in vitro interaction of high and low molecular weight single-chain urokinase-type plasminogen activator with rat liver cells

Gaubius instituut Instituut voor verouderings- en vaatziekten onderzoek TNO (author), Kuiper, J. (author), Rijken, D.C. (author), Munk, G.A. (author), van Berkel, T.J. (author)

The plasma clearance and the interaction of high (HMW) and low (LMW) molecular weight single-chain urokinase-type plasminogen activator (scu-PA) with rat liver cells was determined. 125I-Labeled HMW- and LMW-scu-PA were rapidly cleared from plasma with a half-life of 0.45 min and a maximal liver uptake of 55% of the injected dose. Liver uptake...

article 1992

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Mechanisms of tissue-type plasminogen activator (tPA) clearance by the liver

Gaubius Instituut TNO (author), Otter, M. (author), Kuiper, J. (author), Berkel T.J.C. van, (author), Rijken, D.C. (author)

Chemicals/CAS: mannose receptor; Mannose, 31103-86-3; PLAT protein, human; Receptors, Cell Surface; Receptors, Immunologic; Recombinant Proteins; Tissue Plasminogen Activator, EC 3.4.21.68.

article 1992

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Age-related changes in albumin elimination in female WAG/Rij rats

Instituut voor experimentele gerontologie TNO (author), Horbach, G.J.M.J. (author), Yap, S.H. (author), van Bezooijen, C.F.A. (author)

Albumin elimination rates were determined in 3-, 12-, 24- and 36-month-old female WAG/Rij rats. No change in elimination half-life was found with age. However, as there was an increase in the whole-body albumin pool, a concomitant increase in albumin clearance was observed at between 12 and 36 months of age. It was concluded that the increase in...

article 1983

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Clearance capacity of rat liver Kupffer, endothelial, and parenchymal cells

Praaning-van Dalen, D.P. (author), Brouwer, A. (author), Knook, D.L. (author), Instituut voor experimentele gerontologie TNO (author)

The clearance of five radioactively labeled test substances - polyvinylpyrrolidone, colloidal albumin, antimony sulfur colloid, endotoxin, and heparin - by the reticuloendothelial system was studied after i.v. injection of these substances into rats. The participation of parenchymal, Kupffer, and endothelial liver cells could be determined after...

article 1981