Taste of a Pill

Lee, Nora; Duan, Haichuan; Hébert, Mary F.; Liang, Cui; Rice, Kenneth; Wang, Joanne

doi:10.1074/jbc.m114.570564

Cited by 72 publications

(37 citation statements)

References 29 publications

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“…For instance, it is expressed on the basolateral membrane of hepatocytes and placental epithelium [29,41], but in the lung, it is localized to the luminal membrane of bronchial epithelial cells [42]. In salivary glands, the OCT3 protein is localized at both basolateral and apical membranes of the secretory epithelial cells [43]. …”

Section: Molecular and Functional Characteristics Of Polyspecific mentioning

confidence: 99%

“…Carrier-mediated transport across cell membranes is particularly important for metformin because it is a hydrophilic (LogP=-1.43) drug with very low passive permeability [60]. In vitro and preclinical in vivo studies have demonstrated metformin is a substrate of hepatic OCT1 as well as OCT2, OCT3, MATEs and PMAT [19,43,62,70,72]. Metformin ameliorates hyperglycemia by decreasing hepatic glucose production, reducing gastrointestinal glucose absorption, and improving peripheral sensitivity to insulin [63].…”

Section: Impact Of Octs and Mates On Intracellular Levels Pharmacmentioning

confidence: 99%

“…Saliva drug concentrations have been used for therapeutic drug monitoring and well as illicit drug testing due to the ease of access to the diagnostic fluid and other potential benefits [113–116]. The impact of efflux transporters on salivary drug accumulation has been reported, and we recently demonstrated an impact of uptake transporters, particularly OCT3, in salivary gland drug accumulation, secretion and drug-induced taste disturbance [43,117–121]. …”

Section: Impact Of Octs and Mates On Intracellular Levels Pharmacmentioning

confidence: 99%

“…However, passive diffusion can neither explain salivary secretion of hydrophilic drugs nor account for high drug accumulation in salivary glands. We found that OCT3 is highly expressed in human parotid, submandibular, and sublingual salivary glands [43]. Other polyspecific organic cation transporters, including OCT1, 2, MATEs, and PMAT, are minimally expressed in human or rodent salivary glands.…”

Section: Impact Of Octs and Mates On Intracellular Levels Pharmacmentioning

confidence: 99%

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Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics

Wagner

2016

Pharmacological Research

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Most drugs are intended to act on molecular targets residing within a specific tissue or cell type. Therefore, the drug concentration within the target tissue or cells is most relevant to its pharmacological effect. Increasing evidences suggest that drug transporters not only play a significant role in governing systemic drug levels, but are also an important gate keeper for intra-tissue and intracellular drug concentrations. This review focuses on polyspecific organic cation transporters, which include the organic cation transporters 1-3 (OCT1-3), the multidrug and toxin extrusion proteins 1-2 (MATE1-2) and the plasma membrane monoamine transporter (PMAT). Following an overview of the tissue distribution, transport mechanisms, and functional characteristics of these transporters, we highlight the studies demonstrating the ability of locally expressed OCTs to impact intracellular drug concentrations and directly influence their pharmacological and toxicological activities. Specifically, OCT1-mediated metformin access to its site of action in the liver is impacted by genetic polymorphisms and chemical inhibition of OCT1. The impact of renal OCT2 and MATE1/2-K in cisplatin intrarenal accumulation and nephrotoxicity is reviewed. New data demonstrating the role of OCT3 in salivary drug accumulation and secretion is discussed. Whenever possible, the pharmacodynamic response and toxicological effects is presented and discussed in light of intra-tissue and intracellular drug exposure. Current challenges, knowledge gaps, and future research directions are discussed. Understanding the impact of transporters on intra-tissue and intracellular drug concentrations has important implications for rationale-based optimization of drug efficacy and safety.

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Section: Molecular and Functional Characteristics Of Polyspecific mentioning

confidence: 99%

Section: Impact Of Octs and Mates On Intracellular Levels Pharmacmentioning

confidence: 99%

Section: Impact Of Octs and Mates On Intracellular Levels Pharmacmentioning

confidence: 99%

Section: Impact Of Octs and Mates On Intracellular Levels Pharmacmentioning

confidence: 99%

See 2 more Smart Citations

Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics

Wagner

2016

Pharmacological Research

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“…The ratio of AUC values shown in Table 3 was calculated as AUC fib / AUC sus = AUC 0-t, fibers / AUC 0-t, suspension . The standard error of the mean (SEM) for PK parameters t 1/2z , AUC 0-72h , and AUC 0-∞ were generated using the bootstrap method with modification [39]. Briefly, using the R program, one of the measured ETR concentrations was randomly imputed at each time point to create 10,000 randomly-generated concentration-time profiles.…”

Section: Methodsmentioning

confidence: 99%

Nanoparticle-releasing nanofiber composites for enhanced in vivo vaginal retention

et al. 2017

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Current approaches for topical vaginal administration of nanoparticles result in poor retention and extensive leakage. To overcome these challenges, we developed a nanoparticle-releasing nanofiber delivery platform and evaluated its ability to improve nanoparticle retention in a murine model. We individually tailored two components of this drug delivery system for optimal interaction with mucus, designing (1) mucoadhesive fibers for better retention in the vaginal tract, and (2) PEGylated nanoparticles that diffuse quickly through mucus. We hypothesized that this novel dual-functioning (mucoadhesive/mucus–penetrating) composite material would provide enhanced retention of nanoparticles in the vaginal mucosa. Equivalent doses of fluorescent nanoparticles were vaginally administered to mice in either water (aqueous suspension) or fiber composites, and fluorescent content was quantified in cervicovaginal mucus and vaginal tissue at time points from 24h to 7d. We also fabricated composite fibers containing etravirine-loaded nanoparticles and evaluated the pharmacokinetics over 7d. We found that our composite materials provided approximately 30-fold greater retention of nanoparticles in the reproductive tract at 24h compared to aqueous suspensions. Compared to nanoparticles in aqueous suspension, the nanoparticles in fiber composites exhibited sustained and higher etravirine concentrations after 24h and up to 7d, demonstrating the capabilities of this new delivery platform to sustain nanoparticle release out to 3d and drug retention out to one week after a single administration. This is the first report of nanoparticle-releasing fibers for vaginal drug delivery, as well as the first study of a single delivery system that combines two components uniquely engineered for complementary interactions with mucus.

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Physicochemistry and the Off‐Target Effects of Drug Molecules

Smith¹

2016

Drug Discovery Toxicology

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Taste of a Pill

Cited by 72 publications

References 29 publications

Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics

Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics

Nanoparticle-releasing nanofiber composites for enhanced in vivo vaginal retention

Physicochemistry and the Off‐Target Effects of Drug Molecules

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