In vitro kinetics of amiodarone and its major metabolite in two human liver cell models after acute and repeated treatments. Issue 1 (25th December 2015)

• Record Type: Journal Article
• Authors: Pomponio, Giuliana; Savary, Camille C.; Parmentier, Céline; Bois, Frederic; Guillouzo, André; Romanelli, Luca; Richert, Lysiane; Di Consiglio, Emma; Testai, Emanuela
• Is Part Of: Toxicology in vitro. Volume 30:Issue 1 Part A (2015)
• Page Start: 36
• Page End: 51
• Publication Date: 2015-12-25
• Subjects: AMI amiodarone -- MDEA mono-N-desethylamiodarone -- DDEA di-N-desethylamiodarone -- PHH primary human hepatocytes -- CYP cytochrome P450 -- DMSO dimetylsulfoxide -- MeOH methanol -- HMM Hepatocyte Maintenance Medium -- FCS fetal calf serum -- SW sandwich -- d0 day 0 -- d13 day 13 -- TP time point -- LOD limit of detection -- ADR adverse drug reactions -- PBPK Physiologically Based Pharmacokinetic models -- PBBK physiologically based biokinetic models; Amiodarone -- Biokinetics -- Repeated exposure -- Primary human hepatocytes -- HepaRG cells -- In vitro biokinetic model; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2014.12.012
• Languages: English
• ISSNs: 0887-2333

Abstract

Highlights: Amiodarone biokinetics was studied and modelled in two human liver cells after acute and repeated treatment. Amiodarone bioavailability was influenced by abiotic processes. It is rapidly uptaken and efficiently metabolised to MDEA in HepaRG and in PHH. MDEA accumulated into the cells much more than the parent over time, especially in HepaRG. The treatment induced phospholipidosis in HepaRG. Abstract: The limited value of in vitro toxicity data for the in vivo extrapolation has been often attributed to the lack of kinetic data. Here the in vitro kinetics of amiodarone (AMI) and its mono-N-desethyl (MDEA) metabolite was determined and modelled in primary human hepatocytes (PHH) and HepaRG cells, after single and repeated administration of clinically relevant concentrations. AMI bioavailability was influenced by adsorption to the plastic and the presence of protein in the medium (e.g. 10% serum protein reduced the uptake by half in HepaRG cells). The cell uptake was quick (within 3 h), AMI metabolism was efficient and a dynamic equilibrium was reached in about a week after multiple dosing. In HepaRG cells the metabolic clearance was higher than in PHH and increased over time, as well as CYP3A4. The interindividual variability in MDEA production in PHHs was not proportional to the differences in CYP3A4 activities, suggesting the involvement of other CYPs and/or AMI-related CYP inhibition. After repeated treatment AMI showed a slight potential for bioaccumulation, whereas much higher intracellular MDEA levels accumulated over time, especially in the HepaRG cells, associated with occurrence of phospholipidosis. The knowledge of in vitro biokinetics is important to transform an actual in vitro concentration–effect into an in vivo dose–effect relationship by using appropriate modelling, thus improving the in vitro -to- in vivo extrapolation.