Publications

Consumption and exposure assessment to toothpaste in French families.

The aim of the study was to assess the consumption and the exposure to toothpaste in French families leaving the consumers free to use their own product at home according to their habits. Consumption data were collected on 104 families. 206 adults (103 women and 103 men) and 195 children aged 2-17 participated in the study. Differences in toothpaste consumption depending on gender and on age were highlighted. As an example, frequency data were higher in adult women (2.0 day-1 on average) than in adult men (1.8 day-1 on average); amount per use data were higher in adult men (1.2 g on average) than in adult women (0.9 g on average). The frequency of use and the amount of toothpaste used per application increased with age. The exposure to toothpaste decreased with age. Children aged 2-6 were the most exposed to toothpaste with a P95 value equal to 8.2 mg/kg bw/day. Adult's P95 exposure value was equal to 2.8 mg/kg bw/day. Exposure values were in the same order of magnitude for both genders in children and in adults. These new data will be useful for safety assessors, especially children data which remain scarce. Retrieve the abstract.

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Direct and quantitative evaluation of the humanCYP3A4 contribution (fm) to drug clearance usingthe in vitro SILENSOMES model

Yannick Parmentier, Corinne Pothier, Audrey Delmas, Fabrice Caradec,Marie-Michèle Trancart, Fabrice Guillet, Belkacem Bouaita, ChristopheChesne, J. Brian Houston & Bernard Walther "Direct and quantitative evaluation of the humanCYP3A4 contribution (fm) to drug clearance usingthe in vitro SILENSOMES model", Xenobiotica, Volume 47, pages 562-575, 2016.


Among the different in vitro studies recommended by the regulatory agencies, no goldstandard model can easily and directly measure the quantitative CYP450 contributions to drug biotransformation. In this article, we propose an original strategy, called SilensomesTM, to produce human liver microsomes silenced for one specific CYP450, thanks to specific mechanism-based inhibitors (MBI). Using azamulin as a specific CYP3A4 MBI, we demonstrated the proof of concept that CYP3A4 can be totally, specifically (even against 3A5) and permanently (at least for six years) inhibited by our process. Thus, comparing clearance in control and CYP3A4-SilensomesTM, CYP3A4 contributions were determined for 11 CYP3A4 substrates which correlated with known in vivo contributions and revealed accuracy with less than 10% error. In comparison, contributions determined using recombinant human CYP450 (rhCYP450s) were less accurate (more than 10% error for 30% of the tested CYP3A4 substrates). This easy and ready-to-use in vitro method combines the advantages of existing models (specificity of rhCYP450s and representativeness of HLM) without their drawbacks. The same strategy could be used to silence other major CYP450s one-by-one to provide a complete direct CYP450 quantitative phenotyping kit.


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GABAA receptor activity modulating piperine analogs: In vitro metabolic stability, metabolite identification, CYP450 reaction phenotyping, and protein binding

In a screening of natural products for allosteric modulators of GABAA receptors (γ-aminobutyric acid type A receptor), piperine was identified as a compound targeting a benzodiazepine-independent binding site. Given that piperine is also an activator of TRPV1 (transient receptor potential vanilloid type 1) receptors involved in pain signaling and thermoregulation, a series of piperine analogs were prepared in several cycles of structural optimization, with the aim of separating GABAA and TRPV1 activating properties. We here investigated the metabolism of piperine and selected analogs in view of further cycles of lead optimization. Metabolic stability of the compounds was evaluated by incubation with pooled human liver microsomes, and metabolites were analyzed by UHPLC-Q-TOF-MS. CYP450 isoenzymes involved in metabolism of compounds were identified by reaction phenotyping with Silensomes™. Unbound fraction in whole blood was determined by rapid equilibrium dialysis. Piperine was the metabolically most stable compound. Aliphatic hydroxylation, and N- and O-dealkylation were the major routes of oxidative metabolism. Piperine was exclusively metabolized by CYP1A2, whereas CYP2C9 contributed significantly in the oxidative metabolism of all analogs. Extensive binding to blood constituents was observed for all compounds.

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Direct and quantitative evaluation of the major human CYP contribution (fmCYP) to drug clearance using the in vitro Silensomes™ model.

Yannick Parmentier, Corinne Pothier, Nicola Hewitt, Ludwig Vincent, FabriceCaradec, Jia Liu, Feifei Lin, Marie-Michèle Trancart, Fabrice Guillet, BelkacemBouaita, Christophe Chesne & Bernard Walther, "Direct and quantitative evaluation of the majorhuman CYP contribution (fmCYP) to drugclearance using the in vitro Silensomes™ model", Xenobiotica, Volume 49, Pages 22-35, 2018.

We have applied the concept of using MBIs to produce CYP-Silensomes to quantify the contribution of the major CYPs to drug metabolism (fmCYP). 2. The target CYPs were extensively and selectivity inhibited by the selected MBIs, while non-target CYPs were inhibited by less than 20% of the homologous control activities. Only CYP2D6-Silensomes exhibited a CYP2B6 inhibition that could be easily and efficiently encountered by subtracting the fmCYP2B6 measured using CYP2B6-Silensomes to adjust the fmCYP2D6. 3. To validate the use of a panel of 6 CYP-Silensomes, we showed that the fmCYP values of mono- and multi-CYP metabolised drugs were well predicted, with 70% within ± 15% accuracy. Moreover, the correlation with observed fmCYP values was higher than that for rhCYPs, which were run in parallel using the same drugs (<45% within ±15% accuracy). Moreover, the choice of the RAF substrate in rhCYP predictions was shown to affect the accuracy of the fmCYP measurement. 4. These results support the use of CYP1A2-, CYP2B6-, CYP2C8-, CYP2C9-, CYP2D6 and CYP3A4-Silensomes to accurately predict fmCYP values during the in vitro enzyme phenotyping assays in early, as well as in development, phases of drug development.

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Last posters

  • Cosmetics exposure data - Particular case of children from birth

    3/15/19

    It is commonly accepted that the Skin Surface Area over Body weight ratio (SA/BW) of infants and children is higher as compared with that in adults. Regarding the safety assessment process of cosmetic ingredients, Toxicological Reference Values (TRV) are expressed as mg/kg bw and the change in the ratio of surface area/body weight compared with an adult would give, according to A.G. Renwick (1998), a discrepancy of 2.3-fold for children at birth (except premature infants). Such inter individual variation is already covered by the generally accepted default value of 100 calculated for individual ingredients which is composed of 10 for interspecies variations (4.0 for toxicokinetics) and 10 for human variability, covering toxicokinetic (3.2) and toxicodynamic (3.2) differences between children and adults (A.G. Renwick (1998) and SCCS (2018)). Scheuplein et al. (2002) estimate that an uncertainty factor of 10 applied to this intra-species variability is a sufficiently powerful parameter to take into account child/adult variability, for children over 6 months old. This estimate may not be relevant for children under 6 months of age, in the absence of developmental or systemic toxicity studies. Given the ambiguity of these data, the question was raised whether the use of an increased uncertainty/safety factor would be relevant to cover children at birth exposure to cosmetic ingredients and ensure their safety under normal and reasonably foreseeable conditions of use.

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  • In-silico modelization of compounds interaction with Bile salt Export Pump (BSEP): an alternative approach to predict hepatotoxicity

    3/15/19

    BSEP is an efflux transporter protein present in the hepatocytes membrane that plays important role in bile acid flow from hepatocyte cell into the bile canaliculi (1,2). Impaired BSEP activity due to drug interaction leads to accumulation of bile acid within the hepatocyte cells and results in cholestasis liver injury (DILI)(3). However, due to the lack of a X-ray structure of BSEP, there is no detail information about interaction of compounds with BSEP.

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  • In silico prediction of Structure and compound affinity of Multidrug Resistance-associated Protein 2 (MRP2) for predicting hepatotoxicity.

    3/15/19

    MRP2 is an unidirectional efflux transporter mainly present in liver, that primarily transports organic anions, including drug conjugates and conjugated bilirubin. MRP2 supports a function in the terminal excretion and detoxification of endogenous and xenobiotic organic anions. Due to the lack of a X-ray structure of MRP2, there is no detail information about interaction of compounds with MRP2.

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  • Safety assessment of cosmetic ingredients for skin sensitization using QSAR in silico tool

    3/15/19

    Skin sensitization methods are developed to protect workers and consumers from chemical exposures. In 2012, OECD Test Guideline 168 (TG) addressed the 5 Key Events (KE) of the skin sensitization Adverse Outcome Pathway (AOP)[1]. To respond to cellular and tissue events(KE2, KE3) in vitro alternative methods were well described such as OECD TG 442C (Direct Peptide Reactivity Assay, DPRA); OECD TG 442D (KeratinoSens™) and OECD TG 442E (human Cell Line Activation Test, h-CLAT). The two biomarkers based test SENS-IS and the Genomic Allergic Detection Test (GARD) are under consideration by the OECD for the development of the respective TGs.

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  • Use of SilensomesTM for the analysis of the inhibitory effect of Amiodarone on Warfarin metabolism

    3/1/19

    SilensomesTM correspond to batches of cryopreserved pooled of human liver microsomes (HLM) chemically silenced for one specific CYP450 using a mechanism based inhibitor (MBI) (1). SilensomesTM can be handled like conventional HLM. SilensomesTM allow qualitative CYP phenotyping, quantitative metabolized fraction (fm ) and intrinsic Clearance (Clint ) evaluation. It is well known that alterations of CYP mediated drug metabolism by simultaneous administration of other drugs is one of the most common causes of drug-drug interactions. One of them regards the possible effects of the antiarhythmic drug Amiodarone (AMIO) on the metabolism of warfarin (WRF). WRF is a widely used anticoagulant with a narrow therapeutic index and compounds affecting its metabolism may have serious consequences. WRF is mostly metabolized by CYP2C9, with the formation of different hydroxylated metabolites (OH-WRF) and AMIO is described to inhibit CYP2C9 (2). The studies reported here aimed to an in vitro experimental demonstration of the above prediction, to support the interpretation of the clinical data in a more robust manner. For that, we exploited Control SilensomesTM and CYP2C9 SilensomesTM, studying the involvement of CYP2C9 in the metabolism of S-WRF, and the effects of amiodarone on its metabolism.

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News

    We are launching Wepredic !

    We are launching Wepredic! – A group that gathers key players in in vitro technologies Christophe Chesné, Ph.D, CEO of Biopredic International, is also the founder of Eurosafe, Starlight and Advancells. With their long-standing expertise in in vitro technologies for toxicology and pharmacokinetics, these companies daily help and support world’s leading pharmaceutical, cosmetic and chemical companies. Wepredic has been funded to unite these four brands and deliver in vitro testing solutions that aim to replace laboratory animals. Discover Christophe Chesné’s editorial on the reasons for this strategic move !

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    New logo and new brand identity for Eurosafe !

    As part of re-shaping the brands of the group Wepredic, our parent company, Eurosafe has been given a facelift. Our new logo captures the essence of our business activity: the safety evaluation of cosmetic and of pharmaceutical products!

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    Gingival irritation on a reconstructed model (3D)

    Eurosafe is pleased to inform you that our tests on reconstructed models have been enhanced with a new security screening for all your oral products (e.g. toothpaste, mouthwash): "Gingival irritation on a reconstructed model (3D)".

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