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
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