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The effect of chitosan on the bioaccessibility and intestinal permeability of acyclovir

Kubbinga, M. (author), Augustijns, P. (author), Garcia, M.A. (author), Heinen, C. (author), Wortelboer, H.M. (author), Verwei, M. (author), Langguth, P. (author)

Chitosan is object of pharmaceutical research as a candidate permeability enhancer. However, chitosan was recently shown to reduce the oral bioavailability of acyclovir in humans. The effect of chitosan on two processes determining the oral bioavailability of acyclovir, bioaccessibility and intestinal absorption, was now investigated. Acyclovir...

article 2019

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Evaluation of two dynamic in vitro models simulating fasted and fed state conditions in the upper gastrointestinal tract (TIM-1 and tiny-TIM) for investigating the bioaccessibility of pharmaceutical compounds from oral dosage forms

Verwei, M. (author), Minekus, M. (author), Zeijdner, E. (author), Schilderink, R. (author), Havenaar, R. (author)

Pharmaceutical research needs predictive in vitro tools for API bioavailability in humans. We evaluated two dynamic in vitro gastrointestinal models: TIM-1 and tiny-TIM. Four low-soluble APIs in various formulations were investigated in the TIM systems under fasted and fed conditions. API small-intestinal bioaccessibility profiles were evaluated...

article 2016

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Prediction of in vivo developmental toxicity of all-trans-retinoic acid based on in vitro toxicity data and in silico physiologically based kinetic modeling

Louisse, J. (author), Bosgra, S. (author), Blaauboer, B.J. (author), Rietjens, I.M.C.M. (author), Verwei, M. (author)

The use of laboratory animals for toxicity testing in chemical safety assessment meets increasing ethical, economic and legislative constraints. The development, validation and application of reliable alternatives for in vivo toxicity testing are therefore urgently needed. In order to use toxicity data obtained from in vitro assays for risk...

article 2015

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Predicting carrier-mediated hepatic disposition of rosuvastatin in man by scaling from individual transfected cell-lines in vitro using absolute transporter protein quantification and PBPK modeling.

Bosgra, S. (author), van de Steeg, E. (author), Vlaming, M.L. (author), Verhoeckx, K.C. (author), Huisman, M.T. (author), Verwei, M. (author), Wortelboer, H.M. (author)

In contrast to primary hepatocytes, estimating carrier-mediated hepatic disposition by using a panel of single transfected cell-lines provides direct information on the contribution of the individual transporters to the net disposition. The most direct way to correct for differences in transporter abundance between cell-lines and tissue is by...

article 2014

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In vitro models for the prediction of in vivo performance of oral dosage forms

Kostewicz, E.S. (author), Abrahamsson, B. (author), Brewster, M. (author), Brouwers, J. (author), Butler, J. (author), Carlert, S. (author), Dickinson, P.A. (author), Dressman, J. (author), Holm, R. (author), Klein, S. (author), Mann, J. (author), McAllister, M. (author), Minekus, M. (author), Muenster, U. (author), Müllertz, A. (author), Verwei, M. (author), Vertzoni, M. (author), Weitschies, W. (author), Augustijns, P. (author)

Accurate prediction of the in vivo biopharmaceutical performance of oral drug formulations is critical to efficient drug development. Traditionally, in vitro evaluation of oral drug formulations has focused on disintegration and dissolution testing for quality control (QC) purposes. The connection with in vivo biopharmaceutical performance has...

article 2014

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A new approach to predict human intestinal absorption using porcine intestinal tissue and biorelevant matrices

Westerhout, J. (author), van de Steeg, E. (author), Grossouw, D. (author), Zeijdner, E.E. (author), Krul, C.A.M. (author), Verwei, M. (author), Wortelboer, H.M. (author)

A reliable prediction of the oral bioavailability in humans is crucial and of high interest for pharmaceutical and food industry. The predictive value of currently used in silico methods, in vitro cell lines, ex vivo intestinal tissue and/or in vivo animal studies for human intestinal absorption, however, is often insufficient, especially when...

article 2014

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Prediction of in vivo developmental toxicity of all‑trans‑retinoic acid based on in vitro toxicity data and in silico physiologically based kinetic modeling

Louisse, J. (author), Bosgra, S. (author), Blaauboer, B.J. (author), Rietjens, Y.M.C.M. (author), Verwei, M. (author)

article 2014

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Drug-drug interactions between rosuvastatin and oral antidiabetic drugs occurring at the level of oatp1b1s

van de Steeg, E. (author), Greupink, R. (author), Schreurs, M. (author), Nooijen, I.H.G. (author), Verhoeck, K.C.M. (author), Hanemaaijer, R. (author), Ripken, D. (author), Monshouwer, M. (author), Vlaming, M.L.H. (author), DeGroot, J. (author), Verwei, M. (author), Russel, F.G.M. (author), Huisman, M.T. (author), Wortelboer, H.M. (author)

Organic anion-transporting polypeptide 1B1 (OATP1B1) is an important hepatic uptake transporter, of which the polymorphic variant OATP1B1*15 (Asn130Asp and Val174Ala) has been associated with decreased transport activity. Rosuvastatin is an OATP1B1 substrate and often concomitantly prescribed with oral antidiabetics in the clinic. The aim of...

article 2013

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Human embryonic stem cell-derived test systems for developmental neurotoxicity: A transcriptomics approach

Krug, A.K. (author), Kolde, R. (author), Gaspar, J.A. (author), Rempel, E. (author), Balmer, N.V. (author), Meganathan, K. (author), Vojnits, K. (author), Baquié, M. (author), Waldmann, T. (author), Ensenat-Waser, R. (author), Jagtap, S. (author), Evans, R.M. (author), Julien, S. (author), Peterson, H. (author), Zagoura, D. (author), Kadereit, S. (author), Gerhard, D. (author), Sotiriadou, I. (author), Heke, M. (author), Natarajan, K. (author), Henry, M. (author), Winkler, J. (author), Marchan, R. (author), Stoppini, L. (author), Bosgra, S. (author), Westerhout, J. (author), Verwei, M. (author), Vilo, J. (author), Kortenkamp, A. (author), Hescheler, J. (author), Hothorn, L. (author), Bremer, S. (author), van Thriel, C. (author), Krause, K.-H. (author), Hengstler, J.G. (author), Rahnenführer, J. (author), Leist, M. (author), Sachinidis, A. (author)

Developmental neurotoxicity (DNT) and many forms of reproductive toxicity (RT) often manifest themselves in functional deficits that are not necessarily based on cell death, but rather on minor changes relating to cell differentiation or communication. The fields of DNT/RT would greatly benefit from in vitro tests that allow the identification...

article 2013

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Integrated testing strategy for reproductive toxicity

Wolterbeek, A.P.M. (author), Beker, A.R.C.L. (author), Bosgra, S. (author), Verwei, M. (author), Westerhout, J. (author), Buist, H.E. (author), Kroese, E.D. (author)

article 2012

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Toward in vitro biomarkers for developmental toxicity and their extrapolation to the in vivo situation

Louisse, J. (author), Verwei, M. (author), Woutersen, R.A. (author), Blaauboer, B.J. (author), Rietjens, I.M.C.M. (author)

Introduction: Reliable in vitro and in silico assays as alternatives for in vivo developmental toxicity studies are urgently needed, for the replacement, reduction and refinement (3Rs) of animal use in toxicological research. Therefore, relevant biomarkers for in vivo developmental toxicity in in vitro assays are needed. Areas covered: The...

article 2012

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Relative developmental toxicity potencies of retinoids in the embryonic stem cell test compared with their relative potencies in in vivo and two other in vitro assays for developmental toxicity

Louisse, J. (author), Gönen, S. (author), Rietjens, I.M.C.M. (author), Verwei, M. (author)

The present study determines the relative developmental toxicity potencies of retinoids in the embryonic stem (ES)-D3 cell differentiation assay of the embryonic stem cell test, and compares the outcomes with their relative potencies in in vivo and two other in vitro assays for developmental toxicity. The results reveal that the potency ranking...

article 2011

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Decrease of intracellular pH as possible mechanism of embryotoxicity of glycol ether alkoxyacetic acid metabolites

Louisse, J. (author), Bai, Y. (author), Verwei, M. (author), van de Sandt, J.J.M. (author), Blaauboer, B.J. (author), Rietjens, I.M.C.M. (author), TNO Kwaliteit van Leven (author)

Embryotoxicity of glycol ethers is caused by their alkoxyacetic acid metabolites, but the mechanism underlying the embryotoxicity of these acid metabolites is so far not known. The present study investigates a possible mechanism underlying the embryotoxicity of glycol ether alkoxyacetic acid metabolites using the methoxyacetic acid (MAA)...

article 2010

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The use of in vitro toxicity data and physiologically based kinetic modeling to predict dose-response curves for in vivo developmental toxicity of glycol ethers in rat and man

Louisse, J. (author), de Jong, E. (author), van de Sandt, J.J.M. (author), Blaauboer, B.J. (author), Woutersen, R.A. (author), Piersma, A.H. (author), Rietjens, I.M.C.M. (author), Verwei, M. (author), TNO Kwaliteit van Leven (author)

At present, regulatory assessment of systemic toxicity is almost solely carried out using animal models. The European Commission's REACH legislation stimulates the use of animal-free approaches to obtain information on the toxicity of chemicals. In vitro toxicity tests provide in vitro concentration-response curves for specific target cells,...

article 2010

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Physiologically based pharmacokinetic modeling of cyclohexane as a tool for integrating animal and human test data

Hissink, A.M. (author), Kulig, B.M. (author), Kruse, J. (author), Freidig, A.P. (author), Verwei, M. (author), Muijser, H. (author), Lammers, J.H.C.M. (author), Mckee, R.H. (author), Owen, D.E. (author), Sweeney, L.M. (author), Salmon, F. (author), TNO Kwaliteit van Leven (author)

This report describes a physiologically based pharmacokinetic model for cyclohexane and its use in comparing internal doses in rats and volunteers following inhalation exposures. Parameters describing saturable metabolism of cyclohexane are measured in rats and used along with experimentally determined partition coefficients. The model is...

article 2009

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A review of the implementation of the embryonic stem cell test (EST)

Marx-Stoelting, P. (author), Adriaens, E. (author), Ahr, H.J. (author), Bremer, S. (author), Garthoff, B. (author), Gelbke, H.P. (author), Piersma, A. (author), Pellizzer, C. (author), Reuter, U. (author), Rogiers, V. (author), Schenk, B. (author), Schwengberg, S. (author), Seiler, A. (author), Spielmann, H. (author), Steemans, M. (author), Stedman, D.B. (author), Vanparys, P. (author), Vericat, J.A. (author), Verwei, M. (author), van de Water, F. (author), Weimer, M. (author), Schwarz, M. (author), TNO Kwaliteit van Leven (author)

article 2009

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Relative developmental toxicity of glycol ether alkoxy acid metabolites in the embryonic stem cell test as compared with the in vivo potency of their parent compounds

de Jong, E. (author), Louisse, J. (author), Verwei, M. (author), Blaauboer, B.J. (author), van de Sandt, J.J.M. (author), Woutersen, R.A. (author), Rietjens, I.M.C.M. (author), Piersma, A.H. (author), TNO Kwaliteit van Leven (author)

The embryonic stem cell test (EST) has been proposed as an in vitro assay that might reduce animal experimentation in regulatory developmental toxicology. So far, evaluation of the EST was not performed using compounds within distinct chemical classes. Evaluation within a distinct class of chemically related compounds can define the usefulness...

article 2009

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Model studies for evaluating the neurobehavioral effects of complex hydrocarbon solvents. III. PBPK modeling of white spirit constituents as a tool for integrating animal and human test data

Hissink, A.M. (author), Krüse, J. (author), Kulig, B.M. (author), Verwei, M. (author), Muijser, H. (author), Salmon, F. (author), Leenheers, L.H. (author), Owen, D.E. (author), Lammers, J.H.C.M. (author), Freidig, A.P. (author), McKee, R.H. (author), TNO Kwaliteit van Leven (author)

As part of a project designed to develop a framework for extrapolating acute central nervous system (CNS) effects of hydrocarbon solvents in animals to humans, experimental studies were conducted in rats and human volunteers in which acute CNS effects were measured and toxicokinetic data were collected. A complex hydrocarbon solvent, white...

article 2007

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Development of a QSAR for worst case estimates of acute toxicity of chemically reactive compounds

Freidig, A.P. (author), Dekkers, S. (author), Verwei, M. (author), Zvinavashe, E. (author), Bessems, J.G.M. (author), van de Sandt, J.J.M. (author), TNO Kwaliteit van Leven (author)

Future EU legislations enforce a fast hazard and risk assessment of thousands of existing chemicals. If conducted by means of present data requirements, this assessment will use a huge number of test animals and will be neither cost nor time effective. The purpose of the current research was to develop methods to increase the acceptability of in...

article 2007

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Prediction of in vivo embryotoxic effect levels with a combination of in vitro studies and PBPK modelling

Verwei, M. (author), van Burgsteden, J.A. (author), Krul, C.A.M. (author), van de Sandt, J.J.M. (author), Freidig, A.P. (author), TNO Kwaliteit van Leven (author)

The new EU legislations for chemicals (Registration, Evaluation and Authorization of Chemicals, REACH) and cosmetics (Seventh Amendment) stimulate the acceptance of in vitro and in silico approaches to test chemicals for their potential to cause reproductive effects. In the current study seven compounds with known in vivo developmental effects...

article 2006