Emerging transporters of clinical importance: an update from the International Transporter Consortium

The International Transporter Consortium (ITC) has recently described seven transporters of particular relevance to drug development. Based on the second ITC transporter workshop in 2012, we have identified additional transporters of emerging importance in pharmacokinetics, interference of drugs with transport of endogenous compounds, and drug-drug interactions (DDIs) in humans. The multidrug and toxin extrusion proteins (MATEs, gene symbol SLC47A) mediate excretion of organic cations into bile and urine. MATEs are important in renal DDIs. Multidrug resistance proteins (MRPs or ABCCs) are drug and conjugate efflux pumps, and impaired activity of MRP2 results in conjugated hyperbilirubinemia. The bile salt export pump (BSEP or ABCB11) prevents accumulation of toxic bile salt concentrations in hepatocytes, and BSEP inhibition or deficiency may cause cholestasis and liver injury. In addition, examples are presented on the roles of nucleoside and peptide transporters in drug targeting and disposition

In Vitro and Clinical Evaluations of the Drug-Drug Interaction Potential of a Metabotropic Glutamate 2/3 Receptor Agonist Prodrug with Intestinal Peptide Transporter 1

ABSTRACT Despite peptide transporter 1 (PEPT1) being responsible for the bioavailability for a variety of drugs, there has been little study of its potential involvement in drug-drug interactions. Pomaglumetad methionil, a metabotropic glutamate 2/3 receptor agonist prodrug, utilizes PEPT1 to enhance absorption and bioavailability. In vitro studies were conducted to guide the decision to conduct a clinical drug interaction study and to inform the clinical study design. In vitro investigations determined the prodrug (LY2140023 monohydrate) is a substrate of PEPT1 with K m value of approximately 30 mM, whereas the active moiety (LY404039) is not a PEPT1 substrate. In addition, among the eight known PEPT1 substrates evaluated in vitro, valacyclovir was the most potent inhibitor (IC 50 = 0.46 mM) of PEPT1-mediated uptake of the prodrug. Therefore, a clinical drug interaction study was conducted to evaluate the potential interaction between the prodrug and valacyclovir in healthy subjects. No effect of coadministration was observed on the pharmacokinetics of the prodrug, valacyclovir, or either of their active moieties. Although in vitro studies showed potential for the prodrug and valacyclovir interaction via PEPT1, an in vivo study showed no interaction between these two drugs. PEPT1 does not appear to easily saturate because of its high capacity and expression in the intestine. Thus, a clinical interaction at PEPT1 is unlikely even with a compound with high affinity for the transporter

Small Scale Collaborative Services: The Role of Design in the Development of the Human Smart City Paradigm

Cities are facing disruptive challenges today. All these require smarter solutions and are creating pressure for the public and private sector to deliver innovative services and great expectations are put in the new Smart City paradigm. Most of these solutions keep technologies out of the urban environments, far from being considered components of the urban functioning and, furthermore, even farer from people and their urban spaces. In this framework design is today re-orienting its theories and practices to new kind of design contexts (neighborhoods, streets, squares, cities) where societal challenges are emerging that require different level of changes from everyday life to huge public institutions and complex organizations. This re-orientation is based on a different smart city paradigm that puts people at the center of the cities smartness and recognizes the need for developing micro and contextualized solutions to address larger cities problems in a sociable mode

Emerging Transporters of Clinical Importance: An Update From the International Transporter Consortium

The International Transporter Consortium (ITC) has recently described seven transporters of particular relevance to drug development. Based on the second ITC transporter workshop in 2012, we have identified additional transporters of emerging importance in pharmacokinetics, interference of drugs with transport of endogenous compounds, and drug-drug interactions (DDIs) in humans. The multidrug and toxin extrusion proteins (MATEs, gene symbol SLC47A) mediate excretion of organic cations into bile and urine. MATEs are important in renal DDIs. Multidrug resistance proteins (MRPs or ABCCs) are drug and conjugate efflux pumps, and impaired activity of MRP2 results in conjugated hyperbilirubinemia. The bile salt export pump (BSEP or ABCB11) prevents accumulation of toxic bile salt concentrations in hepatocytes, and BSEP inhibition or deficiency may cause cholestasis and liver injury. In addition, examples are presented on the roles of nucleoside and peptide transporters in drug targeting and disposition

Italianway: An Entrepreneurial Innovation for Hospitality in Contemporary Cities

This chapter is devoted to a specific case of sharing economy in Milan, broadening the vision to include the influence that infrastructuring processes have not only on the complex socio-technical system (scale-up) but also on a single case at local level (scale-down), supporting the authors in a reflection of the impact of the sharing economy on management innovation. We describe Italianway, a Milanese platform that links visitors with the local communities and services to offer an authentic experience of the city; in the creators’ words: “Live like a local, welcome to Milan”. This chapter illustrates the favourable factors of the wider contemporary scenario on local economic growth, enabling the introduction of innovative solutions into a traditional economic system through the hybridisation of the sharing economy approach with and within a given milieu

Genetic Polymorphisms in Human Proton-Dependent Dipeptide Transporter PEPT1: Implications for the Functional Role of Pro 586

ABSTRACT The human proton-dependent dipeptide transporter (PEPT1, gene SLC15A1) is important for intestinal absorption of di-and tripeptides and a variety of peptidomimetic compounds. Using a DNA polymorphism discovery panel of 44 ethnically diverse individuals, nine nonsynonymous and four synonymous coding-region single-nucleotide polymorphisms (SNPs) were identified in PEPT1. HeLa cells were transiently transfected with plasmids constructed by site-directed mutagenesis for each of the nine nonsynonymous variants. Quantitative polymerase chain reaction showed that the mRNA transcription level of all of the mutants was comparable with the mRNA transcription level of the reference sequence in transfected HeLa cells. Functional analysis in transiently transfected HeLa cells revealed that all nonsynonymous variants retained similar pH-dependent activity and K t values for [glycyl-1,2-14 C]glycylsarcosine (GlySar) uptake as the reference PEPT1. In addition, a group of seven peptide-like drugs showed inhibitory effect on Gly-Sar uptake by these variants comparable with the reference, suggesting conserved drug recognition. Of the nine nonsynonymous SNPs, a single SNP (P586L) demonstrated significantly reduced transport capacity as evidenced by a much lower V max value. This was consistent with lower immunoactive protein level (Western analysis) and lower plasma membrane expression (immunocytochemical analysis). Therefore, Pro 586 may have profound effect on PEPT1 translation, degradation, and/or membrane insertion

Foregrounding Learning in Infrastructuring : to Change Worldviews and Practices in the Public Sector

Mutual learning and infrastructuring are two core concepts in Participatory Design (PD), but the relation between them has yet to be explored. In this article, we foreground learning in infrastructuring processes aimed at change in the public sector. Star and Ruhleder’s (1996) framework for first, second, and third level issues is applied as a fruitful way to stage and analyze learning in such processes. The argument is developed through the insights that arose from a 4-year-long infrastructuring process about future library practices. Framed as Co-Labs this process was organized by researchers and officers from the local regional office. This led to adjusted roles for both PD researchers and civil servants working with materials at the operational and strategic levels. The case shows how learning led to profound changes in the regional public sector in the form of less bureaucratic and more participatory experimental and learning-focused worldviews and practices.Urb@ExpSocial Innovation Skån