"Branched Tail" Oxyquinoline Inhibitors of HIF Prolyl Hydroxylase: Early Evaluation of Toxicity and Metabolism Using Liver-on-a-chip.
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.
['Poloznikov|Andrey A|AA|', 'Nikulin|Sergey V|SV|', 'Zakhariants|Arpenik A|AA|', 'Khristichenko|Anna Y|AY|', 'Hushpulian|Dmitry M|DM|', 'Gazizov|Ildar N|IN|', 'Tishkov|Vladimir I|VI|', 'Gazaryan|Irina G|IG|']
D001711:Biotransformation D002460:Cell Line D003577:Cytochrome P-450 Enzyme System D004353:Drug Evaluation, Preclinical D022781:Hepatocytes D006801:Humans D064799:Hypoxia-Inducible Factor-Proline Dioxygenases D056656:Lab-On-A-Chip Devices D008099:Liver D010084:Oxidation-Reduction D064800:Prolyl-Hydroxylase Inhibitors D011804:Quinolines D018675:Toxicity Tests
adaptaquin HIF prolyl hydroxylase inhibitor HepaRG cells CYP2B6 induction early drug-discovery stage oxyquinolines.