Comparison of MDCK-MDR1 and Caco-2 cell based permeability assays for anti-malarial drug screening and drug investigations

Jin, Xiannu; Luong, ThuLan; Reese, Necole; Gaona, Heather; Collazo-Velez, Vanessa; Vuong, Chau; Potter, Brittney; Sousa, Jason; Olmeda, Raul; Li, Qigui; Xie, Lijian; Zhang, Jing; Zhang, Ping; Reichard, Greg; Meléndez, Víctor; Marcsisin, Sean R.; Pybus, Brandon

doi:10.1016/j.vascn.2014.08.002

Cited by 70 publications

(48 citation statements)

References 21 publications

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“…Permeability values of MDR1-MDCK cells for pindolol and timolol were derived from 62 and for quinidine from 63 . For betaxolol, linezolid, prednisolone and theophylline corresponding CaCo-2 cell permeability values were used 61 (recent work indicates that there is a linear relationship between estimated permeability values from CaCo-2 and MDR1-MDCK cells 64–66 ). Fraction excreted unchanged drug as well as drug classes were derived from 67 .…”

Section: Methodsmentioning

confidence: 99%

Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS)

Maaß

Stokes²,

Griffith

et al. 2017

Integr. Biol.

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Microphysiological systems (MPS) provide relevant physiological environments in vitro for studies of pharmacokinetics, pharmacodynamics and biological mechanisms for translational research. Designing multi-MPS platforms is essential to study multi-organ systems. Typical design approaches, including direct and allometric scaling, scale each MPS individually and are based on relative sizes not function. This study’s aim was to develop a new multi-functional scaling approach for integrated multi-MPS platform design for specific applications. We developed an optimization approach using mechanistic modeling and specification of an objective that considered multiple MPS functions, e.g., drug absorption and metabolism, simultaneously to identify system design parameters. This approach informed the design of two hypothetical multi-MPS platforms consisting of gut and liver (multi-MPS platform I) and gut, liver and kidney (multi-MPS platform II) to recapitulate in vivo drug exposures in vitro. This allows establishment of clinically relevant drug exposure-response relationships, a prerequisite for efficacy and toxicology assessment. Design parameters resulting from multi-functional scaling were compared to designs based on direct and allometric scaling. Human plasma time-concentration profiles of eight drugs were used to inform the designs, and profiles of an additional five drugs were calculated to test the designed platforms on an independent set. Multi-functional scaling yielded exposure times in good agreement with in vivo data, while direct and allometric scaling approaches resulted in short exposure durations. Multi-functional scaling allows appropriate scaling from in vivo to in vitro of multi-MPS platforms, and in the cases studied provides designs that better mimic in vivo exposures than standard MPS scaling methods.

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Section: Methodsmentioning

confidence: 99%

Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS)

Maaß

Stokes²,

Griffith

et al. 2017

Integr. Biol.

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“…Primaquine seems to be no different as there are several documented instances of pharmacokinetic drug-drug interactions in the literature (Alving, et al, 1955;Hanboonkunupakarn, et al, 2014;Jin, et al, 2014;Jittamala, et al, 2015;Pukrittayakamee, et al, 2014). The most studied of these interactions is between primaquine and blood stage antimalarial agents administered concurrently.…”

Section: Cyp 2d6 Mediated Primaquine Drug-drug Interactionsmentioning

confidence: 99%

“…Other confounding factors that add to the complexity of studying primaquine interactions is the likelihood of transporter mediated drugdrug interactions. Primaquine has been shown to interact with ABC transporters such as Pglycoprotein (Ambudkar, et al, 1999;Hayeshi, Masimirembwa, Mukanganyama, & Ungell, 2006;Jin, et al, 2014). P-glycoprotein mediated transport can influence drug absorption and distribution.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…P-glycoprotein mediated transport can influence drug absorption and distribution. Interestingly, some of the blood stage antimalarial agents that could interact with primaquine through CYP metabolic pathways, also have the potential to interact with primaquine through P-glycoprotein mediated transport (Ambudkar, et al, 1999;Hayeshi, et al, 2006;Jin, et al, 2014). Primaquine drug-drug interactions are likely complex and involve a multitude of pharmacological factors besides hepatic metabolism.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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Primaquine pharmacology in the context of CYP 2D6 pharmacogenomics: Current state of the art

Marcsisin

Reichard

Pybus

2016

Pharmacology & Therapeutics

Self Cite

103

104

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Primaquine is the only antimalarial drug available to clinicians for the treatment of relapsing forms of malaria. Primaquine development and usage dates back to the 1940s and has been administered to millions of individuals to treat and eliminate malaria infections. Primaquine therapy is not without disadvantages, however, as it can cause life threatening hemolysis in humans with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In addition, the efficacy of primaquine against relapsing malaria was recently linked to CYP 2D6 mediated activation to an active metabolite, the structure of which has escaped definitive identification for over 75years. CYP 2D6 is highly polymorphic among various human populations adding further complexity to a comprehensive understanding of primaquine pharmacology. This review aims to discuss primaquine pharmacology in the context of state of the art understanding of CYP 2D6 mediated 8-aminoquinoline metabolic activation, and shed light on the current knowledge gaps of 8-aminoquinoline mechanistic understanding against relapsing malaria.

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“…[131] Der Assay verwendet eine Zelllinie,d ie die DNA-bindendende Domäne Gal4 exprimiert, welche mit der Ligandenbindungsdomäne des Glucocorticoidrezeptors (GR) und der Tr ansaktivierungsdomäne VP16 gekoppelt ist. [159][160][161] LC-MS kann auch herangezogen werden, um die Internalisierung von Peptiden in Kulturzellen zu quantifizieren, jedoch ist dies ohne Anreicherungsschritte technisch anspruchsvoll. [159][160][161] LC-MS kann auch herangezogen werden, um die Internalisierung von Peptiden in Kulturzellen zu quantifizieren, jedoch ist dies ohne Anreicherungsschritte technisch anspruchsvoll.…”

Section: Methoden Zur Messung Der Zellpenetrationunclassified

Neue Methoden und Designprinzipien für zellgängige Peptide

Peraro

Kritzer

2018

Angewandte Chemie

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Biomoleküle, wie Antikörper, Proteine und Peptide, sind wichtige Werkzeuge in der chemischen Biologie und Ansatzpunkte für die Wirkstoffentwicklung. Sie wurden erfolgreich verwendet, um eine Reihe von extrazellulären Proteinen zu inhibieren, allerdings stellt die Interaktion mit intrazellulären Proteinen eine weit größere Herausforderung dar. In dieser Aufsatz diskutieren wir unterschiedliche chemische Ansätze, die zu zellgängigen Peptiden geführt haben, und identifizieren drei eigenständige Vorgehensweisen: die Maskierung von Rückgratamiden, die Strukturierung von Guanidingruppen und die amphipathische Strukturierung. Wir fassen zusammen, wie anhand großer Datensätze, die in steigendem Maße entstehen, spezifischere Designprinzipien für jede dieser Strategien abgeleitet werden können. Wir beschreiben außerdem Vor‐ und Nachteile gängiger Methoden zur Quantifizierung der Zellpenetration. Abschließend geben wir eine Übersicht über die vielversprechendsten Ansätze für die Anwendung dieser neuen Methoden und Designprinzipien zur Optimierung der zytosolischen Penetration eines bioaktiven Peptids.

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Comparison of MDCK-MDR1 and Caco-2 cell based permeability assays for anti-malarial drug screening and drug investigations

Cited by 70 publications

References 21 publications

Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS)

Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS)

Primaquine pharmacology in the context of CYP 2D6 pharmacogenomics: Current state of the art

Neue Methoden und Designprinzipien für zellgängige Peptide

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