"Branched Tail" Oxyquinoline Inhibitors of HIF Prolyl Hydroxylase: Early Evaluation of Toxicity and Metabolism Using Liver-on-a-chip.
Biotransformation
Cell Line
Cytochrome P-450 Enzyme System
/ metabolism
Drug Evaluation, Preclinical
Hepatocytes
Humans
Hypoxia-Inducible Factor-Proline Dioxygenases
/ antagonists & inhibitors
Lab-On-A-Chip Devices
Liver
/ cytology
Oxidation-Reduction
Prolyl-Hydroxylase Inhibitors
/ chemistry
Quinolines
/ chemistry
Toxicity Tests
/ instrumentation
CYP2B6 induction
HIF prolyl hydroxylase inhibitor
HepaRG cells
adaptaquin
early drug-discovery stage
oxyquinolines.
Journal
Drug metabolism letters
ISSN: 1874-0758
Titre abrégé: Drug Metab Lett
Pays: United Arab Emirates
ID NLM: 101313587
Informations de publication
Date de publication:
2019
2019
Historique:
received:
30
06
2018
revised:
18
10
2018
accepted:
07
11
2018
pubmed:
30
11
2018
medline:
7
1
2020
entrez:
30
11
2018
Statut:
ppublish
Résumé
"Branched tail" oxyquinolines, and adaptaquin in particular, are potent HIF prolyl hydroxylase inhibitors showing promising results in in vivo hemorrhagic stroke models. The further improvement of the potency resulted in identification of a number of adaptaquin analogs. Early evaluation of toxicity and metabolism is desired right at the step of lead selection. The aim of the study is to characterize the toxicity and metabolism of adaptaquin and its new improved analogs. Liver-on-a-chip technology with differentiated HepaRG cells followed by LC-MS detection of the studied compounds and metabolites of the P450 substrate-inhibitor panel for CYP2B6, CYP2C9, CYP2C19, and CYP3A4. The optimized adaptaquin analogs show no toxicity up to a 100-fold increased range over EC50. The drugs are metabolized by CYP3A4 and CYP2B6 as shown with the use of the cytochrome P450 substrate-inhibitor panel designed and optimized for preclinical evaluation of drugs' in vitro biotransformation on a 3D human histotypical cell model using "liver-on-a-chip" technology. Activation of CYP2B6 with the drugs tested has been observed. A scheme for adaptaquin oxidative conversion is proposed. The optimized adaptaquin analogs are suitable for further preclinical trials. Activation of CYP2B6 with adaptaquin and its variants points to a potential increase in Tylenol toxicity if administered together.
Sections du résumé
BACKGROUND
"Branched tail" oxyquinolines, and adaptaquin in particular, are potent HIF prolyl hydroxylase inhibitors showing promising results in in vivo hemorrhagic stroke models. The further improvement of the potency resulted in identification of a number of adaptaquin analogs. Early evaluation of toxicity and metabolism is desired right at the step of lead selection.
OBJECTIVE
The aim of the study is to characterize the toxicity and metabolism of adaptaquin and its new improved analogs.
METHOD
Liver-on-a-chip technology with differentiated HepaRG cells followed by LC-MS detection of the studied compounds and metabolites of the P450 substrate-inhibitor panel for CYP2B6, CYP2C9, CYP2C19, and CYP3A4.
RESULTS
The optimized adaptaquin analogs show no toxicity up to a 100-fold increased range over EC50. The drugs are metabolized by CYP3A4 and CYP2B6 as shown with the use of the cytochrome P450 substrate-inhibitor panel designed and optimized for preclinical evaluation of drugs' in vitro biotransformation on a 3D human histotypical cell model using "liver-on-a-chip" technology. Activation of CYP2B6 with the drugs tested has been observed. A scheme for adaptaquin oxidative conversion is proposed.
CONCLUSION
The optimized adaptaquin analogs are suitable for further preclinical trials. Activation of CYP2B6 with adaptaquin and its variants points to a potential increase in Tylenol toxicity if administered together.
Identifiants
pubmed: 30488807
pii: DML-EPUB-94876
doi: 10.2174/1872312813666181129100950
doi:
Substances chimiques
Prolyl-Hydroxylase Inhibitors
0
Quinolines
0
Cytochrome P-450 Enzyme System
9035-51-2
EGLN1 protein, human
EC 1.14.11.2
Hypoxia-Inducible Factor-Proline Dioxygenases
EC 1.14.11.29
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
45-52Informations de copyright
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.