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Breast cancer resistance protein (BCRP) is expressed in various tissues, such as the gut, liver, kidney and blood brain barrier (BBB), where it mediates the unidirectional transport of substrates to the apical/luminal side of polarized cells. Thereby BCRP acts as an efflux pump, mediating the elimination or restricting the entry of endogenous compounds or xenobiotics into tissues and it plays important roles in drug disposition, efficacy and safety. Bcrp knockout mice (Bcrp−/−) have been used widely to study the role of this transporter in limiting intestinal absorption and brain penetration of substrate compounds. Here we describe the first generation and characterization of a mouse line humanized for BCRP (hBCRP), in which the mouse coding sequence from the start to stop codon was replaced with the corresponding human genomic region, such that the human transporter is expressed under control of the murine Bcrp promoter. We demonstrate robust human and loss of mouse BCRP/Bcrp mRNA and protein expression in the hBCRP mice and the absence of major compensatory changes in the expression of other genes involved in drug metabolism and disposition. Pharmacokinetic and brain distribution studies with several BCRP probe substrates confirmed the functional activity of the human transporter in these mice. Furthermore, we provide practical examples for the use of hBCRP mice to study drug-drug interactions (DDIs). The hBCRP mouse is a promising model to study the in vivo role of human BCRP in limiting absorption and BBB penetration of substrate compounds and to investigate clinically relevant DDIs involving BCRP.
NVS123 is a poorly water-soluble protease 56 inhibitor in clinical development. Data from in vitro hepatocyte studies suggested that NVS123 is mainly metabolized by CYP3A4. As a consequence of limited solubility, NVS123 therapeutic plasma exposures could not be achieved even with high doses and optimized formulations. One approach to overcome NVS123 developability issues was to increase plasma exposure by coadministrating it with an inhibitor of CYP3A4 such as ritonavir. A clinical boost effect was predicted by using physiologically based pharmacokinetic (PBPK) modeling. However, initial boost predictions lacked sufficient confidence because a key parameter, fraction of drug metabolized by CYP3A4 (ƒₘCYP3A4), could not be estimated with accuracy on account of disconnects between in vitro and in vivo preclinical data. To accurately estimate ƒₘCYP3A4 in human, an in vivo boost effect study was conducted using CYP3A4-humanized mouse model which showed a 33- to 56-fold exposure boost effect. Using a top-down approach, human ƒₘCYP3A4 for NVS123 was estimated to be very high and included in the human PBPK modeling to support subsequent clinical study design. The combined use of the in vivo boost study in CYP3A4-humanized mouse model mice along with PBPK modeling accurately predicted the clinical outcome and identified a significant NVS123 exposure boost (∼42-fold increase) with ritonavir.
Divided government is often thought of as causing legislative deadlock. I investigate the link between divided government and economic reforms using a novel data set on welfare reforms in US states between 1978 and 2010. Panel data regressions show that, under divided government, a US state is around 25% more likely to adopt a welfare reform than under unified government. Several robustness checks confirm this counter-intuitive finding. Case study evidence suggests an explanation based on policy competition between governor, senate, and house.
Die Entscheidung in der Rechtssache Bohez /Wiertz bot dem EuGH Gelegenheit, zur Abgrenzung der Anwendungsbereiche von Brüssel I-(jetzt: Brüssel Ia-) und Brüssel IIa-VO Stellung zu nehmen. Den Ausgangspunkt bildete dabei ein familienrechtlicher Sachverhalt, nämlich die zwangsweise Durchsetzung des Umgangsrechts eines Vaters im Hinblick auf seine beiden Kinder. Auf den ersten Blick lag daher eine Anwendung der auf Verfahren betreffend die elterliche Verantwortung bezogenen Brüssel IIa-VO nahe. Andererseits schien auch eine Argumentation denkbar, wonach es sich bei dem zu vollstreckenden Anspruch auf Zahlung des Zwangsgeldes um eine Geldforderung handele, deren Vollstreckung nach der Brüssel I-VO zu erfolgen habe.
Was vordergründig die Ermittlung des einschlägigen EU-Rechtsaktes betraf, erwies sich bei genauerer Betrachtung als Bestimmung der dogmatischen Rechtsnatur des Zwangsgeldes.
Mit der Verabschiedung der Europäischen Güterrechtsverordnung für Ehegatten und eingetragene Partner hat der Unionsgesetzgeber die Vereinheitlichung des Kollisionsrechts in Europa weiter vorangetrieben. Zentraler Baustein beider Rechtsakte ist die Parteiautonomie, die mit Blick auf Eheleute an bewährte Traditionen anknüpft, für Lebenspartner aber eine echte Neuerung bringt.