Use of a non-hepatic cell line highlights limitations associated with cell-based assessment of metabolically induced toxicity:
- Weyers, Carli, Dingle, Laura M K, Wilhelmi, Brendan S, Edkins, Adrienne L, Veale, Clinton G L
- Authors: Weyers, Carli , Dingle, Laura M K , Wilhelmi, Brendan S , Edkins, Adrienne L , Veale, Clinton G L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/160290 , vital:40431 , DOI: 10.1080/01480545.2019.1585869
- Description: Metabolically induced drug-toxicity is a major cause of drug failure late in drug optimization phases. Accordingly, in vitro metabolic profiling of compounds is being introduced at earlier stages of the drug discovery pipeline. An increasingly common method to obtain these profiles is through overexpression of key CYP450 metabolic enzymes in immortalized liver cells, to generate competent hepatocyte surrogates. Enhanced cytotoxicity is presumed to be due to toxic metabolite production via the overexpressed enzyme. However, metabolically induced toxicity is a complex multi-parameter phenomenon and the potential background contribution to metabolism arising from the use of liver cells which endogenously express CYP450 isoforms is consistently overlooked. In this study, we sought to reduce the potential background interference by applying this methodology in kidney-derived HEK293 cells which lack endogenous CYP450 expression.
- Full Text:
- Date Issued: 2020
- Authors: Weyers, Carli , Dingle, Laura M K , Wilhelmi, Brendan S , Edkins, Adrienne L , Veale, Clinton G L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/160290 , vital:40431 , DOI: 10.1080/01480545.2019.1585869
- Description: Metabolically induced drug-toxicity is a major cause of drug failure late in drug optimization phases. Accordingly, in vitro metabolic profiling of compounds is being introduced at earlier stages of the drug discovery pipeline. An increasingly common method to obtain these profiles is through overexpression of key CYP450 metabolic enzymes in immortalized liver cells, to generate competent hepatocyte surrogates. Enhanced cytotoxicity is presumed to be due to toxic metabolite production via the overexpressed enzyme. However, metabolically induced toxicity is a complex multi-parameter phenomenon and the potential background contribution to metabolism arising from the use of liver cells which endogenously express CYP450 isoforms is consistently overlooked. In this study, we sought to reduce the potential background interference by applying this methodology in kidney-derived HEK293 cells which lack endogenous CYP450 expression.
- Full Text:
- Date Issued: 2020
Adsorptive removal of ciprofloxacin and isoniazid from aqueous solution
- Dube, Cyril S, Tandlich, Roman, Wilhelmi, Brendan S
- Authors: Dube, Cyril S , Tandlich, Roman , Wilhelmi, Brendan S
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/76846 , vital:30629 , https://doi.org/10.2478/nbec-2018-0002
- Description: This paper describes study of ciprofloxacin and isoniazid removal from aqueous solutions using coal fly ash (FA), kaolinite, perlite, talc and vermiculite. The adsorptive features of the adsorbents were evaluated for ciprofloxacin and isoniazid with regards to the effects of contact time, pH, the solid/liquid ratio and antibiotic concentration. All adsorbents were sterilised by dry heat before use to avoid the proliferation of antimicrobial resistance by the bacteria present on the adsorbents during experiments. The regression correlation coefficients indicate that the Langmuir model gives the best fit for the sorption of both antibiotics onto FA and talc, ciprofloxacin onto kaolinite, and isoniazid onto perlite and vermiculite with R2 values ranging from 0.908 – 0.999. The Freundlich isotherm best describes the sorption of ciprofloxacin onto vermiculite and isoniazid onto kaolinite with R2 values of 0.999 for both. The Tempkin model best describes the sorption of ciprofloxacin onto perlite with an R2 = 0.997. The values of the Freundlich exponent, 1/n, range from 0.221 – 0.998, indicating a favourable adsorption of ciprofloxacin and isoniazid onto the adsorbents. The heat of sorption, B, calculated from the Temkin plots has values ranging from 0.018 – 10.460 J/mol, indicating a physical adsorption process (physisorption). Adsorption equilibrium was achieved after 30 min for both antibiotics and the kinetic data obtained conforms best to the pseudo-second order equation with R2 values ranging from 0.998 – 0.999. The removal of ciprofloxacin and isoniazid by all adsorbents except FA was strongly influenced by the pH suggesting that electrostatic interactions play a major role in the adsorption processes.
- Full Text:
- Date Issued: 2018
- Authors: Dube, Cyril S , Tandlich, Roman , Wilhelmi, Brendan S
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/76846 , vital:30629 , https://doi.org/10.2478/nbec-2018-0002
- Description: This paper describes study of ciprofloxacin and isoniazid removal from aqueous solutions using coal fly ash (FA), kaolinite, perlite, talc and vermiculite. The adsorptive features of the adsorbents were evaluated for ciprofloxacin and isoniazid with regards to the effects of contact time, pH, the solid/liquid ratio and antibiotic concentration. All adsorbents were sterilised by dry heat before use to avoid the proliferation of antimicrobial resistance by the bacteria present on the adsorbents during experiments. The regression correlation coefficients indicate that the Langmuir model gives the best fit for the sorption of both antibiotics onto FA and talc, ciprofloxacin onto kaolinite, and isoniazid onto perlite and vermiculite with R2 values ranging from 0.908 – 0.999. The Freundlich isotherm best describes the sorption of ciprofloxacin onto vermiculite and isoniazid onto kaolinite with R2 values of 0.999 for both. The Tempkin model best describes the sorption of ciprofloxacin onto perlite with an R2 = 0.997. The values of the Freundlich exponent, 1/n, range from 0.221 – 0.998, indicating a favourable adsorption of ciprofloxacin and isoniazid onto the adsorbents. The heat of sorption, B, calculated from the Temkin plots has values ranging from 0.018 – 10.460 J/mol, indicating a physical adsorption process (physisorption). Adsorption equilibrium was achieved after 30 min for both antibiotics and the kinetic data obtained conforms best to the pseudo-second order equation with R2 values ranging from 0.998 – 0.999. The removal of ciprofloxacin and isoniazid by all adsorbents except FA was strongly influenced by the pH suggesting that electrostatic interactions play a major role in the adsorption processes.
- Full Text:
- Date Issued: 2018
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