title: Investigation of ifosfamide and chloroacetaldehyde renal toxicity through integration of in vitro liver-kidney microfluidic data and pharmacokinetic-system biology models.
abstract: We have integrated in vitro and in silico data to describe the toxicity of chloroacetaldehyde (CAA) on renal cells via its production from the metabolism of ifosfamide (IFO) by hepatic cells. A pharmacokinetic (PK) model described the production of CAA by the hepatocytes and its transport to the renal cells. A system biology model was coupled to the PK model to describe the production of reactive oxygen species (ROS) induced by CAA in the renal cells. In response to the ROS production, the metabolism of glutathione (GSH) and its depletion were modeled by the action of an NFE2L2 gene-dependent pathway. The model parameters were estimated in a Bayesian context via Markov Chain Monte Carlo (MCMC) simulations based on microfluidic experiments and literature in vitro data. Hepatic IFO and CAA in vitro intrinsic clearances were estimated to be 1.85 x 10(-9) μL s(-1) cell(-1) and 0.185 x 10(-9) μL s(-1) cell(-1) ,respectively (corresponding to an in vivo intrinsic IFO clearance estimate of 1.23 l h(-1) , to be compared to IFO published values ranging from 3 to 10 l h(-1) ). After model calibration, simulations made at therapeutic doses of IFO showed CAA renal intracellular concentrations ranging from 11 to 131 μM. Intracellular CAA concentrations above 70 μM induced intense ROS production and GSH depletion. Those responses were time and dose dependent, showing transient and non-linear kinetics. Those results are in agreement with literature data reporting that intracellular CAA toxic concentrations range from 35 to 320 μM, after therapeutic ifosfamide dosing. The results were also consistent with in vitro CAA renal cytotoxicity data.
authors.affiliation: CNRS UMR 7338, Laboratoire de Biomécanique et Bio ingénierie, Université de Technologie de Compiègne, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Leclerc
authors.affiliation: CNRS UMR 7338, Laboratoire de Biomécanique et Bio ingénierie, Université de Technologie de Compiègne, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hamon
authors.affiliation: CNRS UMR 7338, Laboratoire de Biomécanique et Bio ingénierie, Université de Technologie de Compiègne, France.|Chaire de Toxicologie Prédictive, Université de Technologie de Compiègne, France.|Institut National de l'Environnement Industriel et des Risques (INERIS), Unité Modèles pour l'Écotoxicologie et la Toxicologie, Parc ALATA, BP2, 60550, Verneuil en Halatte, France.
authors.forename: Frederic Yves
authors.initials: FY
authors.lastname: Bois
mesh_terms: D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000633:toxicity; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity*; D001499:Bayes Theorem; D002478:Cells, Cultured / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects*; D007069:Ifosfamide / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects*; D044085:Microfluidics / Q000379:methods; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D018906:Antineoplastic Agents, Alkylating; C004656:chloroacetaldehyde; D000079:Acetaldehyde; D007069:Ifosfamide
keywords: Ifosfamide; chloroacetaldehyde; microfluidic biochips; pharmacokinetic model; systems biology