'Branched Tail' Oxyquinoline Inhibitors of HIF Prolyl Hydroxylase: Early Evaluation of Toxicity and Metabolism Using Liver-on-a-chip
| Autor: | I N Gazizov, Anna Yu. Khristichenko, A. A. Zakhariants, Andrey A. Poloznikov, Dmitry M. Hushpulian, Vladimir I. Tishkov, Irina G. Gazaryan, Sergey Nikulin |
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| Rok vydání: | 2019 |
| Předmět: |
CYP2B6
Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science CYP2C19 Pharmacology Cell Line Hypoxia-Inducible Factor-Proline Dioxygenases 03 medical and health sciences 0302 clinical medicine Cytochrome P-450 Enzyme System In vivo Lab-On-A-Chip Devices Toxicity Tests Humans Pharmacology (medical) Biotransformation 030304 developmental biology 0303 health sciences CYP3A4 biology Chemistry Biochemistry (medical) Cytochrome P450 Prolyl-Hydroxylase Inhibitors HIF prolyl-hydroxylase inhibitor In vitro Liver Toxicity Hepatocytes Quinolines biology.protein Oxidation-Reduction 030217 neurology & neurosurgery |
| Zdroj: | Drug Metabolism Letters. 13:45-52 |
| ISSN: | 1872-3128 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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