Physiology-based IVIVE predictions of tramadol from in vitro metabolism data

To predict the tramadol in vivo pharmacokinetics in adults by using in vitro metabolism data and an in vitro-in vivo extrapolation (IVIVE)-linked physiologically-based pharmacokinetic (PBPK) modeling and simulation approach (SimcypA (R)). Tramadol metabolism data was gathered using metabolite formation in human liver microsomes (HLM) and recombinant enzyme systems (rCYP). Hepatic intrinsic clearance (CLint(H)) was (i) estimated from HLM corrected for specific CYP450 contributions from a chemical inhibition assay (model 1); (ii) obtained in rCYP and corrected for specific CYP450 contributions by study-specific intersystem extrapolation factor (ISEF) values (model 2); and (iii) scaled back from in vivo observed clearance values (model 3). The model-predicted clearances of these three models were evaluated against observed clearance values in terms of relative difference of their geometric means, the fold difference of their coefficients of variation, and relative CYP2D6 contribution. Model 1 underpredicted, while model 2 overpredicted the total tramadol clearance by -27 and +22%, respectively. The CYP2D6 contribution was underestimated in both models 1 and 2. Also, the variability on the clearance of those models was slightly underpredicted. Additionally, blood-to-plasma ratio and hepatic uptake factor were identified as most influential factors in the prediction of the hepatic clearance using a sensitivity analysis. IVIVE-PBPK proved to be a useful tool in combining tramadol's low turnover in vitro metabolism data with system-specific physiological information to come up with reliable PK predictions in adults

Raising interoperability among base registries : the evolution of the Linked Base Registry for addresses in Flanders

The transformation of society towards a digital economy and government austerity creates a new context leading to changing roles for both government and private sector. Boundaries between public and private services are blurring, enabling government and private sector to collaborate and share responsibilities. In Belgium, the regional Government of Flanders embedded the re-use of public sector information in its legislation and published a data portal containing well over 4000 Open Datasets. Due to a lack of interoperability, interconnecting and interpreting these sources of information remain challenges for public administrations, businesses and citizens. To dissolve the boundaries between the data silos, the Flemish government applied Linked Data design principles in an operational public sector context. This paper discusses the trends we have identified while ‘rewiring’ the Authentic Source for addresses to a Linked Base Registry. We observed the impact on multiple interoperability levels; namely on the legal, organisational, semantic and technical level. In conclusion Linked Data can increase semantic and technical interoperability and lead to a better adoption of government information in the public and private sector. We strongly believe that the insights from the past thirteen years in the region of Flanders could speed up processes in other countries that are facing the complexity of raising technical and semantic interoperability.This paper is related to the projects ‘OSLO and CRAB as Linked Open Data’ and the ‘Flemish Building Registry’, funded by Flanders Information Agency, Belgium and the program Flanders Radically Digital, Belgium.IMEC Ghent University, Belgiumhttp://www.elsevier.com/locate/websemhj2020Geography, Geoinformatics and Meteorolog

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DMPs on chromosome X. The location data: Illumina probe ID, chromosome, position, strand, UCSC gene symbol, UCSC genetic feature and regulatory feature, are shown alongside the methylation statistics: mean difference in beta, the p values and the BH-adjusted p values. DMPs associated to either PABPC5 or MIR223 are indicated in bold. (XLSX 12 kb

99mTc-mebrofenin disposition in chimeric mice with a humanized liver

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Cell-based models to study hepatic drug metabolism and enzyme induction in humans

Cell-based in vitro models are invaluable tools in elucidating the pharmacokinetic profile of a drug candidate during its drug discovery and development process. As biotransformation is one of the key determinants of a drug's disposition in the body, many in vitro models to study drug metabolism have been established, and others are still being developed and validated. This review is aimed at providing the reader with a concise overview of the characteristics and optimal application of established and emerging in vitro cell-based models to study human drug metabolism and induction of drug metabolising enzymes in the liver. The strengths and weaknesses of liver-derived models, such as primary hepatocytes, either freshly isolated or cryopreserved, and from adult or fetal donors, precision-cut liver slices, and cell lines, including immortalised cells, reporter cell lines, hepatocarcinoma-derived cell lines and recombinant cell lines, are discussed. Relevant cell culture configuration aspects as well as other models such as stem cell-derived hepatocyte-like cells and humanised animal models are also reviewed. The status of model development, their acceptance by health authorities and recommendations for the most appropriate use of the models are presented.status: publishe

Non-invasive method to obtain blood curves of 99mTc-mebrofenin

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Data science and healthcare

status: publishe