金丝桃苷
药代动力学
化学
毒物动力学
药理学
CYP3A4型
氯菊酯
毒物动力学
药效学
CYP2A6
细胞色素P450
基于生理学的药代动力学模型
生物
新陈代谢
生物化学
贯叶连翘
杀虫剂
农学
作者
Jochen Kühnl,Thi Phuong Tao,Katrin Brandmair,Silke Gerlach,Thamée Rings,Ursula Müller‐Vieira,Julia Przibilla,Camille Géniès,Carine Jaques-Jamin,Andreas Schepky,Uwe Marx,Nicola J. Hewitt,Ilka Maschmeyer
出处
期刊:Toxicology
[Elsevier]
日期:2021-01-01
卷期号:448: 152637-152637
被引量:31
标识
DOI:10.1016/j.tox.2020.152637
摘要
Microphysiological systems (MPS) aim to mimic the dynamic microenvironment and the interaction between tissues. While MPS exist for investigating pharmaceuticals, the applicability of MPS for cosmetics ingredients is yet to be evaluated. The HUMIMIC Chip2 (“Chip2″), is the first multi-organ chip technology to incorporate skin models, allowing for the topical route to be tested. Therefore, we have used this model to analyze the impact of different exposure scenarios on the pharmacokinetics and pharmacodynamics of two topically exposed chemicals, hyperforin and permethrin. The Chip2 incorporated reconstructed human epidermis models (EpiDerm™) and HepaRG-stellate spheroids. Initial experiments using static incubations of single organoids helped determine the optimal dose. In the Chip2 studies, parent and metabolites were analyzed in the circuit over 5 days after application of single and repeated topical or systemic doses. The gene expression of relevant xenobiotic metabolizing enzymes in liver spheroids was measured to reflect toxicodynamics effects of the compounds in liver. The results show that 1) metabolic capacities of EpiDerm™ and liver spheroids were maintained over five days; 2) EpiDerm™ model barrier function remained intact; 3) repeated application of compounds resulted in higher concentrations of parent chemicals and most metabolites compared to single application; 4) compound-specific gene induction e.g. induction of CYP3A4 by hyperforin depended on the application route and frequency; 5) different routes of application influenced the systemic concentrations of both parents and metabolites in the chip over the course of the experiment; 6) there was excellent intra- and inter-lab reproducibility. For permethrin, a process similar to the excretion in a human in vivo study could be simulated which was remarkably comparable to the in vivo situation. These results support the use of the Chip2 model to provide information on parent and metabolite disposition that may be relevant to risk assessment of topically applied cosmetics ingredients.
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