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  • Transporters are important ta http www apexbt com media

    2022-01-24

    Transporters are important targets for devising new therapies, optimizing existing therapies, and helping understand the toxicities of certain drugs. Given the well-documented role of transporters in restricting the distribution of drugs, modulating the relevant transporters could enhance the permeation of drugs to the Clindamycin HCl to clinically relevant levels (Lee et al., 2001). Understanding how drugs commonly used in the management of acute brain injuries affect the function of transporters could determine how and to what extent those drugs should be utilized clinically (Nigam, 2015; Nigam et al., 2015a). In a similar way as drug-drug interactions, transporter-mediated drug-metabolite interactions and drug-nutrient interactions could provide new targets for intervention and/or optimize the way we use existing therapies (Nigam, 2015). This review examines membrane transporters as regulators of the movement of injury mediators, signaling molecules, and therapeutic drugs between cells and across biological barriers in the context of TBI. Also, specific issues in children such as transporter ontology and therapeutic strategies in TBI that target membrane transporters will be highlighted. Currently, the amount known about transporters in TBI and in particular pediatric TBI—as will be shown—is limited, and thus this represents a potentially important gap for future investigation.
    Membrane transporters in the CNS Membrane transporters are divided into two major super-families: the solute carrier (SLC) transporters which rely on electrochemical (passive or created by secondary-active transporters) or ionic gradients to facilitate translocation of substrates across barriers, and the adenosine triphosphate (ATP)-binding cassette (ABC) transporters which utilize ATP to traffic various substrates across membranes (Moitra and Dean, 2011; Hediger et al., 2013). Because of the critical role transporters play in determining the pharmacokinetics of drug molecules and the implication in the efficacy and safety of drugs, an understanding of drug-transporter interactions is required in the FDA drug approval process and is an area of intense research (Giacomini et al., 2010, Nigam, 2015). However, the role of transporters in mediating physiological and pathological processes related to endogenous substrates has remained relatively understudied. A growing body of evidence is revealing the importance of transporters in regulating the movement of endogenous molecules including metabolites, nutrients, signaling molecules, and biosynthesis and degradation by-products between cells, tissues and body fluid compartments (Loscher and Potschka, 2005b; Loscher and Potschka, 2005a; Moitra and Dean, 2011; Cesar-Razquin et al., 2015; Nigam, 2015; Nigam et al., 2015b). Transporters have been described as forming a “remote signaling and sensing system” to regulate the communication between organs, tissues and cells (Ahn and Nigam, 2009; Wu et al., 2011; Nigam et al., 2015a; Nigam et al., 2015b). This role makes transporters significant players not only in maintaining homeostasis but also in the initiation, progression, and resolution of pathological processes. For example, it is estimated that one in four of the SLC transporters is implicated in Mendelian diseases (Lin et al., 2015). Numerous studies including several genome wide association studies have demonstrated the association of genetic variants in SLC and ABC transporters with complex human diseases including diabetes, neurodegenerative diseases, liver diseases, cardiovascular diseases and cancer (Pedersen, 2007; Zutz et al., 2009; Kubitz et al., 2012; Hediger et al., 2013; Cesar-Razquin et al., 2015; Lin et al., 2015; Qosa et al., 2015; Schaedler et al., 2015). There are also several examples of FDA-approved drugs and drugs in development that target transporters directly or indirectly (Cesar-Razquin et al., 2015). Interactions with transporters have also been described as the mechanism behind the toxicity of some commonly used drugs such as simvastatin. In some cases, transporter-mediated toxicity has led to the discontinuation of clinical development of drugs (Link et al., 2008; Zhang et al., 2014).