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|Title:||In vitro-to-in vivo correlation of the skin penetration, liver clearance and hepatotoxicity of caffeine|
|Authors:||GAJEWSKA MONIKA; PAINI ALICIA; SALA BENITO Jose'; BURTON JULIEN; WORTH Andrew; URANI Chiara; BRIESEN Heiko; SCHRAMM Karl-Werner|
|Citation:||FOOD AND CHEMICAL TOXICOLOGY vol. 75 p. 39–49|
|Publisher:||PERGAMON-ELSEVIER SCIENCE LTD|
|Type:||Articles in periodicals and books|
|Abstract:||This work illustrates the use of Physiologically-Based Toxicokinetic (PBTK) modelling in in vitro-to-in vivo correlation (IVIVC) of kinetic measures of caffeine skin penetration and liver metabolism, as well as dose metrics of caffeine-induced HepaRG toxicity. We applied a PBTK model calibrated for the Caucasian population to quantify the differences in in vitro and in vivo skin absorption and liver metabolism rates by means of a simple correlation factor. We developed a multi-scale computational approach by linking the PBTK model with a Virtual Cell-Based (VCB) Assay to relate an external oral and dermal dose with an internal dose-dependent liver toxicity, measured in vitro as HepaRG cell viability. The results revealed higher in vivo skin permeation profiles than those determined in vitro using identical in vitro and in vivo exposure conditions. Literature in vitro liver metabolism rates were higher than the optimized in vivo rates with respect to available caffeine plasma concentrations. Finally, HepaRG cell viability was shown to decrease only slightly for external caffeine doses in the 5-200 mg range, assuming a 4.56 mg/mL in ethanol/propylene glycol vehicle after both exposure types. We modelled single human exposure to single doses of caffeine only. The approaches described in the present paper provide a promising means of performing in vitro -to- in vivo correlations that may contribute to a reduction of animal experimentation in the chemical risk assessment process.|
|JRC Directorate:||Institute for Health and Consumer Protection Historical Collection|
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