In vitro kinetics of amiodarone and its major metabolite in two human liver cell models after acute and repeated treatments

Pomponio, Giuliana; Savary, Camille; Parmentier, Céline; Romanelli, L.; Richert, Lysiane; Consiglio, Emma Di; Testai, Emanuela

doi:10.1016/j.tiv.2014.12.012

Cited by 34 publications

(36 citation statements)

References 44 publications

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“…As shown in when used in a plated configuration can maintain their metabolic competence for longer duration and support the measurement of clearance for low-clearance chemicals (Smith, 2012). When used in sandwich configuration they can maintain their features for days Pomponio et al, 2015). However, plated hepatocytes are not typically For the sake of harmonisation and understanding there is a need to agree on which enzymes need to be characterised, the experimental methodology that should be applied and the probe chemical(s) that should be used for each enzyme.…”

Section: Biological Test System Related Componentsmentioning

confidence: 83%

“…lipophilicity, charge and size), can bind to the proteins in the medium thus affecting the free unbound (bioavailable) concentration and the cell uptake (Pomponio et al 2015;Armitage et al, 2014). Several methods are commonly used to measure plasma protein binding including equilibrium dialysis, ultrafiltration and ultracentrifugation, solid phase microextraction (SPME), the latter to measure serum constituent binding of drugs in the in vitro exposure medium (Broeders et al, 2011).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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Establishing a systematic framework to characterise in vitro methods for human hepatic metabolic clearance

Gouliarmou¹,

Lostia²,

Coecke³

et al. 2018

Toxicology in Vitro

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Hepatic metabolic clearance is one of the most important factors driving the overall kinetics of chemicals including substances used in various product categories such as pesticides, biocides, pharmaceuticals, and cosmetics. A large number of in vitro systems from purified isozymes and subcellular organelles to hepatocytes in simple cultures and in complex scaffold setups are available for measuring hepatic metabolic clearance for different applications. However, there is currently no approach for systematically characterising and comparing these in vitro methods in terms of their design, applicability and performance. To address this, existing knowledge in the field of in vitro human hepatic metabolic clearance methods was gathered and analysed in order to establish a framework to systematically characterise methods based on a set of relevant components. An analogous framework would be also applicable for non-human in vitro systems. The components are associated with the biological test systems used (e.g. subcellular or cells), the in vitro method (e.g. number of cells, test item solubility), related analytical techniques, data interpretation methods (based on substrate depletion/metabolite formation), and performance assessments (precision and accuracy of clearance measurements). To facilitate the regulatory acceptance of this class of methods, it is intended that the framework provide the basis of harmonisation work within the OECD.

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Section: Biological Test System Related Componentsmentioning

confidence: 83%

Section: Accepted Manuscriptmentioning

confidence: 99%

Establishing a systematic framework to characterise in vitro methods for human hepatic metabolic clearance

Gouliarmou¹,

Lostia²,

Coecke³

et al. 2018

Toxicology in Vitro

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“…Three concentrations were then tested for further experiments, the highest corresponding to the IC 20 value. IC 10 or IC 20 values are commonly selected for use in early in vitro toxicology studies (Liguori et al, 2008;Pomponio et al, 2015). When IC 20 values could not be determined because of absence of toxicity, higher concentrations were tested.…”

Section: Resultsmentioning

confidence: 99%

Early Alterations of Bile Canaliculi Dynamics and the Rho Kinase/Myosin Light Chain Kinase Pathway Are Characteristics of Drug-Induced Intrahepatic Cholestasis

Burbank

Burban

Sharanek

et al. 2016

Drug Metabolism and Disposition

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Intrahepatic cholestasis represents 20%-40% of drug-induced injuries from which a large proportion remains unpredictable. We aimed to investigate mechanisms underlying drug-induced cholestasis and improve its early detection using human HepaRG cells and a set of 12 cholestatic drugs and six noncholestatic drugs. In this study, we analyzed bile canaliculi dynamics, Rho kinase (ROCK)/myosin light chain kinase (MLCK) pathway implication, efflux inhibition of taurocholate [a predominant bile salt export pump (BSEP) substrate], and expression of the major canalicular and basolateral bile acid transporters. We demonstrated that 12 cholestatic drugs classified on the basis of reported clinical findings caused disturbances of both bile canaliculi dynamics, characterized by either dilatation or constriction, and alteration of the ROCK/MLCK signaling pathway, whereas noncholestatic compounds, by contrast, had no effect. Cotreatment with ROCK inhibitor Y-27632 [4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride] and MLCK activator calmodulin reduced bile canaliculi constriction and dilatation, respectively, confirming the role of these pathways in drug-induced intrahepatic cholestasis. By contrast, inhibition of taurocholate efflux and/or human BSEP overexpressed in membrane vesicles was not observed with all cholestatic drugs; moreover, examples of noncholestatic compounds were reportedly found to inhibit BSEP. Transcripts levels of major bile acid transporters were determined after 24-hour treatment. BSEP, Na-taurocholate cotransporting polypeptide, and organic anion transporting polypeptide B were downregulated with most cholestatic and some noncholestatic drugs, whereas deregulation of multidrug resistance-associated proteins was more variable, probably mainly reflecting secondary effects. Together, our results show that cholestatic drugs consistently cause an early alteration of bile canaliculi dynamics associated with modulation of ROCK/MLCK and these changes are more specific than efflux inhibition measurements alone as predictive nonclinical markers of drug-induced cholestasis.

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“…Therefore, it might be postulated that cytokine effects could be amplified by incubating the cells in serum-and DMSO-free medium. However, previous studies have shown that in presence of 2% serum limited changes if any were observed in drug biokinetics in HepaRG cells (Broeders et al, 2015;Pomponio et al, 2015).…”

Section: Accepted Manuscriptmentioning

confidence: 93%

Pro-inflammatory cytokines enhance dilatation of bile canaliculi caused by cholestatic antibiotics

Sharanek

Burban

Ciriaci

2019

Toxicology in Vitro

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Many drugs can induce liver injury, characterized by hepatocellular, cholestatic or mixed hepatocellular-cholestatic lesions. While an inflammatory stress is known to aggravate hepatocellular injury caused by some drugs much less evidence exists for cholestatic features. In this study, the influence of pro-inflammatory cytokines (IL-6, IL-1β and TNF-α), either individually or combined, on cytotoxic and cholestatic properties of antibiotics was evaluated using differentiated HepaRG cells. Six antibiotics of various chemical structures and known to cause cholestasis and/or hepatocellular injury in clinic were investigated. Caspase-3 activity was increased with all these tested hepatotoxic drugs and except with erythromycin, was further augmented in presence of cytokines mainly when these were co-added as a mixture. TNF-α and IL-1β aggravated cytotoxicity of TVX more than IL-6. Bile canaliculi (BC) dilatation induced by cholestatic drugs was increased by co-treatment with IL-6 and IL-1β but not with TNF-α. Reduced accumulation of carboxy-dichlorofluorescein, a substrate of the multi-drug resistance-associated protein 2, in antibiotic-induced dilatated BC, was further extended in presence of individual or mixed cytokines. In conclusion, our data demonstrate that pro-inflammatory cytokines either individually or in mixture, can modulate cholestatic and/or cytotoxic responses to antibiotics and that the extent of these effects is dependent on the cytokine and the cholestatic antibiotic.

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In vitro kinetics of amiodarone and its major metabolite in two human liver cell models after acute and repeated treatments

Cited by 34 publications

References 44 publications

Establishing a systematic framework to characterise in vitro methods for human hepatic metabolic clearance

Establishing a systematic framework to characterise in vitro methods for human hepatic metabolic clearance

Early Alterations of Bile Canaliculi Dynamics and the Rho Kinase/Myosin Light Chain Kinase Pathway Are Characteristics of Drug-Induced Intrahepatic Cholestasis

Pro-inflammatory cytokines enhance dilatation of bile canaliculi caused by cholestatic antibiotics

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