title: In vitro-to-in vivo correlation of the skin penetration, liver clearance and hepatotoxicity of caffeine.
abstract: This work illustrates the use of Physiologically-Based Toxicokinetic (PBTK) modelling for the healthy Caucasian population in in vitro-to-in vivo correlation of kinetic measures of caffeine skin penetration and liver clearance (based on literature experiments), as well as dose metrics of caffeine-induced measured HepaRG toxicity. We applied a simple correlation factor to quantify the in vitro and in vivo differences in the amount of caffeine permeated through the skin and concentration-time profiles of caffeine in the liver. We developed a multi-scale computational approach by linking the PBTK model with a Virtual Cell-Based Assay to relate an external oral and dermal dose with the measured in vitro HepaRG cell viability. The results revealed higher in vivo skin permeation profiles than those determined in vitro using identical exposure conditions. Liver clearance of caffeine derived from in vitro metabolism rates was found to be much slower than the optimised in vivo clearance with respect to caffeine plasma concentrations. Finally, HepaRG cell viability was shown to remain almost unchanged for external caffeine doses of 5-400 mg for both oral and dermal absorption routes. We modelled single exposure to caffeine only.
authors.affiliation: Systems Toxicology Unit, EURL ECVAM, Institute for Health and Consumer Protection, European Commission, Joint Research Centre, Ispra, VA 21027, Italy; Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt, Department für Biowissenschaften, TUM, Weihenstephaner Steig 23, Freising 85350, Germany. Electronic address: monika_gajewska84@wp.pl.
authors.forename: M
authors.initials: M
authors.lastname: Gajewska
authors.affiliation: Systems Toxicology Unit, EURL ECVAM, Institute for Health and Consumer Protection, European Commission, Joint Research Centre, Ispra, VA 21027, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Paini
authors.affiliation: Systems Toxicology Unit, EURL ECVAM, Institute for Health and Consumer Protection, European Commission, Joint Research Centre, Ispra, VA 21027, Italy.
authors.forename: J V
authors.initials: JV
authors.lastname: Sala Benito
authors.affiliation: Systems Toxicology Unit, EURL ECVAM, Institute for Health and Consumer Protection, European Commission, Joint Research Centre, Ispra, VA 21027, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Burton
authors.affiliation: Systems Toxicology Unit, EURL ECVAM, Institute for Health and Consumer Protection, European Commission, Joint Research Centre, Ispra, VA 21027, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Worth
authors.affiliation: Department of Earth and Environmental Sciences, University of Milano Bicocca, Piazza della Scienza 1, Milano, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Urani
authors.affiliation: Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt, Lehrstuhl für Systemverfahrenstechnik, TUM, Weihenstephaner Steig 23, Freising 85350, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Briesen
authors.affiliation: Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt, Department für Biowissenschaften, TUM, Weihenstephaner Steig 23, Freising 85350, Germany; Molecular EXposomics (MEX), Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, Neuherberg D-85764, Germany.
authors.forename: K-W
authors.initials: KW
authors.lastname: Schramm
mesh_terms: D000279:Administration, Cutaneous; D000284:Administration, Oral; D002110:Caffeine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects*
chemical_list: D002110:Caffeine
keywords: Caffeine; In vitro-to-in vivo correlation; Physiologically-Based Toxicokinetic (PBTK) modelling; Virtual cell-based assay