Addressing the ADME Challenges of Compound Loss in a PDMS-Based Gut-on-Chip Microphysiological System.

Autor: Carius P; Department Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach, Germany., Weinelt FA; Department Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach, Germany., Cantow C; Department Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach, Germany., Holstein M; Department Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach, Germany., Teitelbaum AM; Department Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach, Germany., Cui Y; Department Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach, Germany.
Jazyk: angličtina
Zdroj: Pharmaceutics [Pharmaceutics] 2024 Feb 20; Vol. 16 (3). Date of Electronic Publication: 2024 Feb 20.
DOI: 10.3390/pharmaceutics16030296
Abstrakt: Microphysiological systems (MPSs) are promising in vitro technologies for physiologically relevant predictions of the human absorption, distribution, metabolism, and excretion (ADME) properties of drug candidates. However, polydimethylsiloxane (PDMS), a common material used in MPSs, can both adsorb and absorb small molecules, thereby compromising experimental results. This study aimed to evaluate the feasibility of using the PDMS-based Emulate gut-on-chip to determine the first-pass intestinal drug clearance. In cell-free PDMS organ-chips, we assessed the loss of 17 drugs, among which testosterone was selected as a model compound for further study based on its substantial ad- and absorptions to organ chips and its extensive first-pass intestinal metabolism with well-characterized metabolites. A gut-on-chip model consisting of epithelial Caco-2 cells and primary human umbilical vein endothelial cells (HUVECs) was established. The barrier integrity of the model was tested with reference compounds and inhibition of drug efflux. Concentration-time profiles of testosterone were measured in cell-free organ chips and in gut-on-chip models. A method to deduce the metabolic clearance was provided. Our results demonstrate that metabolic clearance can be determined with PDMS-based MPSs despite substantial compound loss to the chip. Overall, this study offers a practical protocol to experimentally assess ADME properties in PDMS-based MPSs.
Databáze: MEDLINE
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