Organ-on-a-chip: Determine feasibility of a human liver microphysiological model to assess long-term steroid metabolites in sports drug testing

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Organ-on-a-chip : Determine feasibility of a human liver microphysiological model to assess long-term steroid metabolites in sports drug testing. / Görgens, Christian; Ramme, Anja Patricia; Guddat, Sven; Schrader, Yvonne; Winter, Annika; Dehne, Eva-Maria; Horland, Reyk; Thevis, Mario.

in: Drug testing and analysis, 10.09.2021, S. 1-8.

Publikationen: Beitrag in FachzeitschriftZeitschriftenaufsätzeForschungBegutachtung

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@article{b4b83b19753640399568121706829481,
title = "Organ-on-a-chip: Determine feasibility of a human liver microphysiological model to assess long-term steroid metabolites in sports drug testing",
abstract = "A fundamental challenge in preventive doping research is the study of metabolic pathways of substances banned in sport. However, the pharmacological predictions obtained by conventional in vitro or in vivo animal studies are occasionally of limited transferability to humans according to an inability of in vitro models to mimic higher order system physiology or due to various species-specific differences using animal models. A more recently established technology for simulating human physiology is the {"}organ-on-a-chip{"} principle. In a multichannel microfluidic cell culture chip, 3-dimensional tissue spheroids, which can constitute artificial and interconnected microscale organs, imitate principles of the human physiology. The objective of this study was to determine if the technology is suitable to adequately predict metabolic profiles of prohibited substances in sport. As model compounds, the frequently misused anabolic steroids, stanozolol and dehydrochloromethyltestosterone (DHCMT) were subjected to human liver spheroids in microfluidic cell culture chips. The metabolite patterns produced and circulating in the chip media were then assessed by LC-HRMS/(MS) at different time points of up to 14 days of incubation at 37°C. The overall profile of observed glucurono-conjugated stanozolol metabolites excellently matched the commonly found urinary pattern of metabolites, including 3'OH-stanozolol-glucuronide and stanozolol-N-glucuronides. Similarly, but to a lower extent, the DHCMT metabolic profile was in agreement with phase-I and phase-II biotransformation products regularly seen in postadministration urine specimens. In conclusion, this pilot study indicates that the {"}organ-on-a-chip{"} technology provides a high degree of conformity with traditional human oral administration studies, providing a promising approach for metabolic profiling in sports drug testing.",
keywords = "doping, in vitro metabolism study, liver spheroids/organoids, mass spectrometry, organ-on-a-chip",
author = "Christian G{\"o}rgens and Ramme, {Anja Patricia} and Sven Guddat and Yvonne Schrader and Annika Winter and Eva-Maria Dehne and Reyk Horland and Mario Thevis",
note = "{\textcopyright} 2021 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.",
year = "2021",
month = sep,
day = "10",
doi = "10.1002/dta.3161",
language = "English",
pages = "1--8",
journal = "Drug testing and analysis",
issn = "1942-7603",
publisher = "John Wiley & Sons, Ltd",

}

RIS

TY - JOUR

T1 - Organ-on-a-chip

T2 - Determine feasibility of a human liver microphysiological model to assess long-term steroid metabolites in sports drug testing

AU - Görgens, Christian

AU - Ramme, Anja Patricia

AU - Guddat, Sven

AU - Schrader, Yvonne

AU - Winter, Annika

AU - Dehne, Eva-Maria

AU - Horland, Reyk

AU - Thevis, Mario

N1 - © 2021 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.

PY - 2021/9/10

Y1 - 2021/9/10

N2 - A fundamental challenge in preventive doping research is the study of metabolic pathways of substances banned in sport. However, the pharmacological predictions obtained by conventional in vitro or in vivo animal studies are occasionally of limited transferability to humans according to an inability of in vitro models to mimic higher order system physiology or due to various species-specific differences using animal models. A more recently established technology for simulating human physiology is the "organ-on-a-chip" principle. In a multichannel microfluidic cell culture chip, 3-dimensional tissue spheroids, which can constitute artificial and interconnected microscale organs, imitate principles of the human physiology. The objective of this study was to determine if the technology is suitable to adequately predict metabolic profiles of prohibited substances in sport. As model compounds, the frequently misused anabolic steroids, stanozolol and dehydrochloromethyltestosterone (DHCMT) were subjected to human liver spheroids in microfluidic cell culture chips. The metabolite patterns produced and circulating in the chip media were then assessed by LC-HRMS/(MS) at different time points of up to 14 days of incubation at 37°C. The overall profile of observed glucurono-conjugated stanozolol metabolites excellently matched the commonly found urinary pattern of metabolites, including 3'OH-stanozolol-glucuronide and stanozolol-N-glucuronides. Similarly, but to a lower extent, the DHCMT metabolic profile was in agreement with phase-I and phase-II biotransformation products regularly seen in postadministration urine specimens. In conclusion, this pilot study indicates that the "organ-on-a-chip" technology provides a high degree of conformity with traditional human oral administration studies, providing a promising approach for metabolic profiling in sports drug testing.

AB - A fundamental challenge in preventive doping research is the study of metabolic pathways of substances banned in sport. However, the pharmacological predictions obtained by conventional in vitro or in vivo animal studies are occasionally of limited transferability to humans according to an inability of in vitro models to mimic higher order system physiology or due to various species-specific differences using animal models. A more recently established technology for simulating human physiology is the "organ-on-a-chip" principle. In a multichannel microfluidic cell culture chip, 3-dimensional tissue spheroids, which can constitute artificial and interconnected microscale organs, imitate principles of the human physiology. The objective of this study was to determine if the technology is suitable to adequately predict metabolic profiles of prohibited substances in sport. As model compounds, the frequently misused anabolic steroids, stanozolol and dehydrochloromethyltestosterone (DHCMT) were subjected to human liver spheroids in microfluidic cell culture chips. The metabolite patterns produced and circulating in the chip media were then assessed by LC-HRMS/(MS) at different time points of up to 14 days of incubation at 37°C. The overall profile of observed glucurono-conjugated stanozolol metabolites excellently matched the commonly found urinary pattern of metabolites, including 3'OH-stanozolol-glucuronide and stanozolol-N-glucuronides. Similarly, but to a lower extent, the DHCMT metabolic profile was in agreement with phase-I and phase-II biotransformation products regularly seen in postadministration urine specimens. In conclusion, this pilot study indicates that the "organ-on-a-chip" technology provides a high degree of conformity with traditional human oral administration studies, providing a promising approach for metabolic profiling in sports drug testing.

KW - doping

KW - in vitro metabolism study

KW - liver spheroids/organoids

KW - mass spectrometry

KW - organ-on-a-chip

UR - https://www.mendeley.com/catalogue/c58890f4-f7e1-3aab-aed7-27378dc785d2/

U2 - 10.1002/dta.3161

DO - 10.1002/dta.3161

M3 - Journal articles

C2 - 34505743

SP - 1

EP - 8

JO - Drug testing and analysis

JF - Drug testing and analysis

SN - 1942-7603

ER -

ID: 6204676