ABSTRACT:The direct thrombin inhibitor melagatran is formed from ximelagatran via two intermediate metabolites, OH-melagatran and ethylmelagatran. The biotransformation of ximelagatran does not involve cytochrome P450 isoenzymes, and it has been suggested that a reported interaction with erythromycin may instead be mediated by transport proteins. A pig model that simultaneously enables bile collection, sampling from three blood vessels and perfusion of a jejunal segment, was used to investigate the biotransformation of ximelagatran and the effect of erythromycin on the intestinal and hepatobiliary transport of ximelagatran and its metabolites. The pigs received enteral ximelagatran (n ‫؍‬ 6), enteral ximelagatran together with erythromycin (n ‫؍‬ 6), i.v. ximelagatran (n ‫؍‬ 4), or i.v. melagatran (n ‫؍‬ 4). The plasma exposure of the intermediates was found to depend on the route of ximelagatran administration. Erythromycin increased the area under the plasma concentration-time curve (AUC) of melagatran by 45% and reduced its biliary clearance from 3.0 ؎ 1.3 to 1.5 ؎ 1.1 ml/min/kg. Extensive biliary exposure of melagatran and ethylmelagatran, mediated by active transport, was evident from the 100-and 1000-fold greater AUC, respectively, in bile than in plasma. Intestinal efflux transporters seemed to be of minor importance for the disposition of ximelagatran and its metabolites considering the high estimated f abs of ximelagatran (80 ؎ 20%) and the negligible amount of the compounds excreted in the perfused intestinal segment. These findings suggest that transporters located at the sinusoidal and/or canalicular membranes of hepatocytes determine the hepatic disposition of ximelagatran and its metabolites, and are likely to mediate the ximelagatran-erythromycin pharmacokinetic interaction.Ximelagatran was the first oral direct thrombin inhibitor to reach the market. As an oral anticoagulant, it had the potential to become an alternative to warfarin and other vitamin K antagonists; however, because of safety concerns involving hepatotoxicity, ximelagatran was withdrawn in 2006. Warfarin currently has an important role in the prevention and treatment of thromboembolic events but is unfortunately also associated with a variable pharmacokinetic and pharmacodynamic response, delayed onset and offset of action, numerous drug-drug interactions, and serious safety issues (Hawkins, 2004;Greenblatt and von Moltke, 2005). The narrow therapeutic index of warfarin and the many sources of variability require monitoring of the anticoagulant effect to maintain blood levels within the therapeutic range. Because of these difficulties and the severe consequences of thrombosis, it is clear that there is a need for new oral anticoagulants. Ximelagatran was developed to improve the low and highly variable bioavailability of the reversible, direct thrombin inhibitor melagatran (Gustafsson et al., 2001). The hydrophilic carboxylic acid and amidine functions of melagatran were protected by introducing an ethylester residue and the less ...

Membrane transporters play crucial roles in the cellular uptake and efflux of an array of small molecules including nutrients, environmental toxins, and many clinically used drugs. We hypothesized that common genetic variation in the proximal promoter regions of transporter genes contribute to observed variation in drug response. A total of 579 polymorphisms were identified in the proximal promoters (−250 to +50 bp) and flanking 5′ sequence of 107 transporters in the ATP Binding Cassette (ABC) and Solute Carrier (SLC) superfamilies in 272 DNA samples from ethnically diverse populations. Many transporter promoters contained multiple common polymorphisms. Using a sliding window analysis, we observed that, on average, nucleotide diversity (π) was lowest at approximately 300 bp upstream of the transcription start site, suggesting that this region may harbor important functional elements. The proximal promoters of transporters that were highly expressed in the liver had greater nucleotide diversity than those that were highly expressed in the kidney consistent with greater negative selective pressure on the promoters of kidney transporters. Twenty-one promoters were evaluated for activity using reporter assays. Greater nucleotide diversity was observed in promoters with strong activity compared to promoters with weak activity, suggesting that weak promoters are under more negative selective pressure than promoters with high activity. Collectively, these results suggest that the proximal promoter region of membrane transporters is rich in variation and that variants in these regions may play a role in interindividual variation in drug disposition and response.

Science and Technology Studies (STS) has been surprisingly slow to become widely known and deployed in the field of education. Yet STS has a rich array of concepts and analytical methods to offer to studies of: knowledge practices and epistemic cultures; the interrelationship between states and knowledge; regulatory practices, governance and institutions; and classrooms, pedagogy, teaching and learning. Most importantly, it provides a fresh perspective on how power operates in ordering societies, disciplining actors and promoting ideas and practices. In this paper, we provide an introduction to STS and elaborate what it offers education scholars. Using examples from the emerging body of STS work in the field of education, and in particular from the papers in this special issue, we argue that STS is not only useful, but an exciting and generative form of critiqueone that is especially suited to investigating contemporary issues in education policies and practices.

In this paper, we explore the improvisations made in examination practices in higher education during the pandemic of 2020. Drawing on STS, we start from the theoretical assumption that examinations constitute an obligatory passage point in universities and colleges: a sacred point which students need to pass if they want to gain recognized qualifications. We base our analysis of higher education examinations on cases from six countries around the world: Australia, Belgium, Chile, India, Sweden and the UK. We use the analytical heuristic of choreography to follow the movements, tensions and resistance of the ‘emergency examinations’ as well as the re-orderings of actors and stages that have inevitably occurred. In our analytical stories we see the interplay between the maintenance of fixed and sacred aspects of examinations and the fluidity of improvisations aimed at meeting threats of spreading Covid-19. These measures have forced the complex network of examinations both to reinforce some conventional actors and to assemble new actors and stages, thus creating radically new choreographies. Although higher education teaching and didactics are being framed as a playground for pedagogical innovation with digital technologies, it is clear from our data that not all educational activities can be so easily replicated.

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