title: Biokinetics in repeated-dosing in vitro drug toxicity studies.
abstract: The aim of the EU FP7 Predict-IV project was to improve the predictivity of in vitro assays for unwanted effects of drugs after repeated dosing. The project assessed the added benefit of integrating long-lived in vitro organotypic cell systems with 'omics' technologies and in silico modelling, including systems biology and pharmacokinetic assessments. RPTEC/TERT1 kidney cells, primary rat and human hepatocytes, HepaRG liver cells and 2D and 3D primary brain cultures were dosed daily or every other day for 14 days to a selection of drugs varying in their mechanism of pharmacological action. Since concentration-effect relationships not only depend on the activity of the drug or the sensitivity of the target, but also on the distribution of compounds in the in vitro system, the concentration of a selection of drugs in cells, microtitre plate plastic and medium was measured over time. Results, reviewed in this paper, indicate that lipophilic drugs bind significantly to plastic labware. A few drugs, including less lipophilic drugs, bind to cell-attachment matrices. Chemicals that reach high concentrations in cells, including cyclosporin A and amiodarone, significantly accumulate over time after repeated dosing, partly explaining their increased toxicity after repeated dosing, compared to a single dose.
authors.affiliation: Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands. Electronic address: N.I.Kramer@uu.nl.
authors.forename: Nynke I
authors.initials: NI
authors.lastname: Kramer
authors.affiliation: Mechanism of Toxicity Unit, Environment and Primary Prevention Department, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Emma
authors.initials: E
authors.lastname: Di Consiglio
authors.affiliation: Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Bas J
authors.initials: BJ
authors.lastname: Blaauboer
authors.affiliation: Mechanism of Toxicity Unit, Environment and Primary Prevention Department, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Testai
mesh_terms: D000818:Animals; D001711:Biotransformation / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004847:Epithelial Cells; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology; D018675:Toxicity Tests
chemical_list: D002352:Carrier Proteins
keywords: Biokinetics; In vitro; Predict-IV; Quantitative in vitro–in vivo extrapolation; Repeated dosing