Pharmaceutical Metabolism in Fish: Using a 3-D Hepatic In Vitro Model to Assess Clearance

Autor: Awadhesh N. Jha, Wendy M. Purcell, Simon K. Jackson, Stewart F. Owen, Matthew G. Baron, A. John Moody, Malcolm J. Hetheridge, Kate S. Mintram
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Trout
Enzyme Metabolism
Drug Evaluation
Preclinical
lcsh:Medicine
Pharmacology
Biochemistry
Drug Metabolism
Tandem Mass Spectrometry
Medicine and Health Sciences
lcsh:Science
Enzyme Chemistry
Biotransformation
Multidisciplinary
biology
Fishes
Propranolol
Enzymes
Carbamazepine
Liver
Phenylbutazone
Osteichthyes
Oncorhynchus mykiss
Vertebrates
Models
Animal
Female
Metabolic Pathways
medicine.drug
Research Article
Metoprolol
Diclofenac
Fish Biology
Xenobiotics
03 medical and health sciences
medicine
Organoid
Fish Physiology
Animals
Animal Physiology
Xenobiotic Metabolism
Pharmacokinetics
Diazepam
lcsh:R
Organisms
Biology and Life Sciences
Proteins
biology.organism_classification
Atenolol
In vitro
Vertebrate Physiology
Kinetics
030104 developmental biology
Metabolism
Enzymology
lcsh:Q
Zoology
Drug metabolism
Water Pollutants
Chemical
Zdroj: PLoS ONE
PLoS ONE, Vol 12, Iss 1, p e0168837 (2017)
ISSN: 1932-6203
Popis: At high internal doses, pharmaceuticals have the potential for inducing biological/pharmacological effects in fish. One particular concern for the environment is their potential to bioaccumulate and reach pharmacological levels; the study of these implications for environmental risk assessment has therefore gained increasing attention. To avoid unnecessary testing on animals, in vitro methods for assessment of xenobiotic metabolism could aid in the ecotoxicological evaluation. Here we report the use of a 3-D in vitro liver organoid culture system (spheroids) derived from rainbow trout to measure the metabolism of seven pharmaceuticals using a substrate depletion assay. Of the pharmaceuticals tested, propranolol, diclofenac and phenylbutazone were metabolised by trout liver spheroids; atenolol, metoprolol, diazepam and carbamazepine were not. Substrate depletion kinetics data was used to estimate intrinsic hepatic clearance by this spheroid model, which was similar for diclofenac and approximately 5 fold higher for propranolol when compared to trout liver microsomal fraction (S9) data. These results suggest that liver spheroids could be used as a relevant and metabolically competent in vitro model with which to measure the biotransformation of pharmaceuticals in fish; and propranolol acts as a reproducible positive control.
Databáze: OpenAIRE
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