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.

Antioxidants in liver health

“…However, this enzyme produces other metabolites such as theobromine, theophylline, and 1,3,7-trimethyluric acid. Other enzymes such as CYPs 1A1 and 2E1 participate in caffeine metabolism [78] .…”

Use of human liver and EpiSkin™ S9 subcellular fractions as a screening assays to compare the in vitro hepatic and dermal metabolism of 47 cosmetics‐relevant chemicals

“…While metabolism in the skin is regarded as negligible for caffeine, as skin expresses little CYP1A2 (Gajewska et al, 2015;Gajewska, Worth, Urani, Briesen, & Schramm, 2014;Genies et al, 2018), it may be expected to be formed in in vitro hepatic test systems. However, in present our experiments, caffeine was not metabolized by liver S9 or PHH.…”

Non-ablative fractional laser assists cutaneous delivery of small- and macro-molecules with minimal bacterial infection risk

“…The vehicle medium was the same with that used in the in vitro permeation experiment. The application period was 6 h, which was shorter than that of the in vitro permeation study since the in vivo condition usually shows a faster drug delivery compared to the in vitro status (Lin et al, 2011;Gajewska et al, 2015). The animal was then sacrificed, and the treated skin area was excised.…”