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Impact of T-2 toxin and zearalenone on the pharmacokinetics of midazolam as CYP3A probe drug in an in vivo porcine animal model

Wim Schelstraete (UGent) , Mathias Devreese (UGent) and Siska Croubels (UGent)
Author
Organization
Abstract
Cytochrome P450 enzymes (CYP450) are important catalyzing proteins, involved in the biotransformation and elimination of endogenous and xenobiotic compounds. However, ingestion of xenobiotics like drugs, food, or food-contaminants, can alter the CYP450 activity. Consequently, co-ingestion of drug and/or feed can lead to altered disposition of the victim drug, leading to either less effectiveness or toxic responses. Nonetheless, regarding drug-food contaminant interactions, literature reports are scarce. Mycotoxins are an example of feed contaminants which are highly prevalent secondary metabolite produced by several fungal species (1). Pigs are a very sensitive species towards the effect of mycotoxins, such as T-2 toxin (T-2) and zearalenone (ZEA). In addition, the pig has been increasingly proposed as a valuable animal model in pharmaceutical and toxicological research, due to its resemblance in anatomy and physiology with humans(2,3). Previous work at our laboratory has shown that T-2 and ZEA can potently inhibit CYP3A activities in porcine microsomes (4). The present study aimed to evaluate the potentially in vivo impact of T-2 and ZEA on the drug metabolizing CYP3A enzymes. Eight pigs (7 weeks of age, 4 males and 4 females) were fed with control feed or feed contaminated with T-2 or ZEA for a two week period. Subsequently midazolam, a CYP3A probe substrate, was intravenously administered and blood samples collected at regular time intervals. After a two day rest period, an oral dose was given and blood samples collected as before. Afterwards pigs were euthanized and liver and intestinal mucosa samples (duodenum, jejunum, and ileum) were collected for preparation of microsomes. Plasma concentration-time data and in vitro assessment of the CYP450 activity will be used to model the impact on the pharmacokinetics of midazolam. The results will be presented at the congress.
Keywords
midazolam, mycotoxins, cytochrome p450

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Chicago
Schelstraete, Wim, Mathias Devreese, and Siska Croubels. 2018. “Impact of T-2 Toxin and Zearalenone on the Pharmacokinetics of Midazolam as CYP3A Probe Drug in an in Vivo Porcine Animal Model.” In Mycotoxin Workshop, 40th, Abstracts.
APA
Schelstraete, W., Devreese, M., & Croubels, S. (2018). Impact of T-2 toxin and zearalenone on the pharmacokinetics of midazolam as CYP3A probe drug in an in vivo porcine animal model. Mycotoxin workshop, 40th, Abstracts. Presented at the 40th Mycotoxin workshop.
Vancouver
1.
Schelstraete W, Devreese M, Croubels S. Impact of T-2 toxin and zearalenone on the pharmacokinetics of midazolam as CYP3A probe drug in an in vivo porcine animal model. Mycotoxin workshop, 40th, Abstracts. 2018.
MLA
Schelstraete, Wim, Mathias Devreese, and Siska Croubels. “Impact of T-2 Toxin and Zearalenone on the Pharmacokinetics of Midazolam as CYP3A Probe Drug in an in Vivo Porcine Animal Model.” Mycotoxin Workshop, 40th, Abstracts. 2018. Print.
@inproceedings{8612703,
  abstract     = {Cytochrome P450 enzymes (CYP450) are important catalyzing proteins, involved in the biotransformation and elimination of endogenous and xenobiotic compounds. However, ingestion of xenobiotics like drugs, food, or food-contaminants, can alter the CYP450 activity. Consequently, co-ingestion of drug and/or feed can lead to altered disposition of the victim drug, leading to either less effectiveness or toxic responses. Nonetheless, regarding drug-food contaminant interactions, literature reports are scarce. Mycotoxins are an example of feed contaminants which are highly prevalent secondary metabolite produced by several fungal species (1). Pigs are a very sensitive species towards the effect of mycotoxins, such as T-2 toxin (T-2) and zearalenone (ZEA). In addition, the pig has been increasingly proposed as a valuable animal model in pharmaceutical and toxicological research, due to its resemblance in anatomy and physiology with humans(2,3). Previous work at our laboratory has shown that T-2 and ZEA can potently inhibit CYP3A activities in porcine microsomes (4). 
The present study aimed to evaluate the potentially in vivo impact of T-2 and ZEA on the drug metabolizing CYP3A enzymes. Eight pigs (7 weeks of age, 4 males and 4 females) were fed with control feed or feed contaminated with T-2 or ZEA for a two week period. Subsequently midazolam, a CYP3A probe substrate, was intravenously administered and blood samples collected at regular time intervals. After a two day rest period, an oral dose was given and blood samples collected as before. Afterwards pigs were euthanized and liver and intestinal mucosa samples (duodenum, jejunum, and ileum) were collected for preparation of microsomes. Plasma concentration-time data and in vitro assessment of the CYP450 activity will be used to model the impact on the pharmacokinetics of midazolam. The results will be presented at the congress.},
  author       = {Schelstraete, Wim and Devreese, Mathias and Croubels, Siska},
  booktitle    = {Mycotoxin workshop, 40th, Abstracts},
  keywords     = {midazolam,mycotoxins,cytochrome p450},
  language     = {eng},
  location     = {Munich, Germany},
  title        = {Impact of T-2 toxin and zearalenone on the pharmacokinetics of midazolam as CYP3A probe drug in an in vivo porcine animal model},
  year         = {2018},
}