Tissue Distribution and Characterization of Drug-Related Material in Rats and Dogs after Repeated Oral Administration of Casopitant

Pagliarusco, Sabrina; Martinucci, Silvia; Bordini, Ellenia; Miraglia, Lidia; Cufari, Domenico; Ferrari, Luca; Pellegatti, Mario

doi:10.1124/dmd.110.035063

Cited by 7 publications

(5 citation statements)

References 38 publications

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“…Surprisingly few good data on this are available in the open literature, though in some cases one can see that the variation in concentration of a drug in different tissues (e.g., as measured by tissue:plasma ratio) can be massive (e.g., Miraglia et al, 2010; Oballa et al, 2011; Pagliarusco et al, 2011; Pfefferkorn et al, 2012). Note that when these kinds of measurements are made directly there is a highly heterogeneous distribution of drugs between different cells in the same tissue (e.g., Khatib-Shahidi et al, 2006; Cornett et al, 2008; Nilsson et al, 2010; Römpp et al, 2010, 2011; Castellino et al, 2011; Marko-Varga et al, 2011, 2012; Ait-Belkacem et al, 2012; Shahidi-Latham et al, 2012; El-Mashtoly et al, 2014; Gessel et al, 2014).…”

Section: We Propose Some Candidate Discriminating Experiments That Admentioning

confidence: 99%

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

Kell¹,

Oliver²

2014

Front. Pharmacol.

148

169

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One approach to experimental science involves creating hypotheses, then testing them by varying one or more independent variables, and assessing the effects of this variation on the processes of interest. We use this strategy to compare the intellectual status and available evidence for two models or views of mechanisms of transmembrane drug transport into intact biological cells. One (BDII) asserts that lipoidal phospholipid Bilayer Diffusion Is Important, while a second (PBIN) proposes that in normal intact cells Phospholipid Bilayer diffusion Is Negligible (i.e., may be neglected quantitatively), because evolution selected against it, and with transmembrane drug transport being effected by genetically encoded proteinaceous carriers or pores, whose “natural” biological roles, and substrates are based in intermediary metabolism. Despite a recent review elsewhere, we can find no evidence able to support BDII as we can find no experiments in intact cells in which phospholipid bilayer diffusion was either varied independently or measured directly (although there are many papers where it was inferred by seeing a covariation of other dependent variables). By contrast, we find an abundance of evidence showing cases in which changes in the activities of named and genetically identified transporters led to measurable changes in the rate or extent of drug uptake. PBIN also has considerable predictive power, and accounts readily for the large differences in drug uptake between tissues, cells and species, in accounting for the metabolite-likeness of marketed drugs, in pharmacogenomics, and in providing a straightforward explanation for the late-stage appearance of toxicity and of lack of efficacy during drug discovery programmes despite macroscopically adequate pharmacokinetics. Consequently, the view that Phospholipid Bilayer diffusion Is Negligible (PBIN) provides a starting hypothesis for assessing cellular drug uptake that is much better supported by the available evidence, and is both more productive and more predictive.

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Section: We Propose Some Candidate Discriminating Experiments That Admentioning

confidence: 99%

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

Kell¹,

Oliver²

2014

Front. Pharmacol.

148

169

View full text Add to dashboard Cite

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“…Casopitant is a chemical and thus is metabolized into multiple metabolites in the liver. It is possible that some of the metabolites have pharmacological activity, and produce these effects (Miraglia et al, ; Pagliarusco et al, ).…”

Section: Discussionmentioning

confidence: 99%

The Potential Role for Corticosterone in the Induction of Cleft Palate in Mice After Treatment With a Selective NK‐1 Receptor Antagonist, Casopitant (GW679769B)

Ziejewski¹,

Solomon²,

Stanislaus³

et al. 2011

Birth Defects Research Pt B

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“…This means that transporter-dependent uptake could have implications for many targeted therapies, from inhibitors of tyrosine kinases to PARPs ( Box 1 ) to PI3-kinases ( Karaman et al, 2008 ; Lannutti et al, 2011 ; Knezevic et al, 2016 ). Similarly, high transporter expression could explain tissue-selective drug accumulation and associated toxicity in non-target tissues ( Pagliarusco et al, 2011 ). Although relevant for all therapeutic compounds, the high inter-patient variability of transporter expression in cancer ( Fig.…”

Section: Transporters In Drug Uptake and Effluxmentioning

confidence: 99%

Membrane transporters in cell physiology, cancer metabolism and drug response

Alam,

Doherty,

Ortega-Prieto

et al. 2023

Disease Models &Amp; Mechanisms

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By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic state of the cell. With more than 450 members, the Solute Carriers (SLCs) are the largest transporter super-family, clustering into families with different substrate specificities and regulatory properties. Cells of different types are, therefore, able to tailor their transporter expression signatures depending on their metabolic requirements, and the physiological importance of these proteins is illustrated by their mis-regulation in a number of disease states. In cancer, transporter expression is heterogeneous, and the SLC family has been shown to facilitate the accumulation of biomass, influence redox homeostasis, and also mediate metabolic crosstalk with other cell types within the tumour microenvironment. This Review explores the roles of membrane transporters in physiological and malignant settings, and how these roles can affect drug response, through either indirect modulation of sensitivity or the direct transport of small-molecule therapeutic compounds into cells.

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Tissue Distribution and Characterization of Drug-Related Material in Rats and Dogs after Repeated Oral Administration of Casopitant

Cited by 7 publications

References 38 publications

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

The Potential Role for Corticosterone in the Induction of Cleft Palate in Mice After Treatment With a Selective NK‐1 Receptor Antagonist, Casopitant (GW679769B)

Membrane transporters in cell physiology, cancer metabolism and drug response

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