Demonstration of the first‐pass metabolism in the skin of the hair dye, 4‐amino‐2‐hydroxytoluene, using the Chip2 skin–liver microphysiological model

Abstract

We used TissUse's HUMIMIC Chip2 microfluidic model, incorporating reconstructed skin models and liver spheroids, to investigate the impact of consumer‐relevant application scenarios on the metabolic fate of the hair dye, 4‐amino‐2‐hydroxytoluene (AHT). After a single topical or systemic application of AHT to Chip2 models, medium was analysed for parent and metabolites over 5 days. The metabolic profile of a high dose (resulting in a circuit concentration of 100 μM based on 100% bioavailability) of AHT was the same after systemic and topical application to 96‐well EpiDerm™ models. Additional experiments indicated that metabolic capacity of EpiDerm™ models were saturated at this dose. At 2.5 μM, concentrations of AHT and several of its metabolites differed between application routes. Topical application resulted in a higher Cmax and a 327% higher area under the curve (AUC) of N‐acetyl‐AHT, indicating a first‐pass effect in the EpiDerm™ models. In accordance with in vivo observations, there was a concomitant decrease in the Cmax and AUC of AHT‐O‐sulphate after topical, compared with systemic application. A similar alteration in metabolite ratios was observed using a 24‐well full‐thickness skin model, EpiDermFT™, indicating that a first‐pass effect was also possible to detect in a more complex model. In addition, washing the EpiDermFT™ after 30 min, thus reflecting consumer use, decreased the systemic exposure to AHT and its metabolites. In conclusion, the skin–liver Chip2 model can be used to (a) recapitulate the first‐pass effect of the skin and alterations in the metabolite profile of AHT observed in vivo and (b) provide consumer‐relevant data regarding leave‐on/rinse‐off products.

Implementing organ-on-chip in a next-generation risk assessment of chemicals: a review

“…First, scaffold free techniques such as hanging drops, magnetic levitation and spheroid microplates with ultra-low attachment coating enable the cells to freely grow prior to seeding in OoCs. This technique is especially applicable for open accessible culture compartments as this layout allows direct seeding of bigger aggregates as demonstrated for liver spheroids (Lasli et al 2019 ; Jang et al 2019a ; Kostrzewski et al 2020 ; Tao et al 2021 ). Second, scaffold-based techniques which use hard material-based polymers or hydrogel supports that mimic the extra cellular matrix (ECM) and enables the cells to properly attach and differentiate (Jensen and Teng 2020 ).…”

Studying metabolism with multi-organ chips: new tools for disease modelling, pharmacokinetics and pharmacodynamics

“…An initial approach of endothelization in a two-organ (liver and skin) model in 2015 enabled the evaluation of oral exposure with troglitazone to liver-intestine co-cultures as well systemic liver-skin co-cultures [106]. There exist other instances of ADMET studies being performed in MOCs [70,95,101,[107][108][109][110]; however, no ADMET study has been performed so far with the presence of the endothelial component. More recently, Ingber and colleagues described a quantitative PK study in a vascularized organ-chip, characterizing the data from a first-pass MOC model perfusing a universal blood substitute between endothelium-lined vascular channels [50,111]: an arteriovenous reservoir enabled mimicry of drug distribution and dilution through the entire vasculature.…”

Research and Development of Microphysiological Systems in Japan Supported by the AMED-MPS Project

“…TissUse (Berlin, Gremany) 12 , a company which originated from Technische Universität Berlin, provides HUMIMIC chips and control units for cell culture, biopsies, tissue sections, etc., according to the user's needs. Co-culture of multiple organs is possible, with reports published on skin and liver culture (Tao et al, 2021 ). InShpero (Schlieren, Switzerland) 13 offers 3D InSight TM using spheroids.…”