Functional assessment of the effects of CYP3A4 variants on acalabrutinib metabolism in vitro
説明
We aimed (i) to study the effects of genetic polymorphism of cytochrome P450 3A4 (CYP3A4) and drug interactions on acalabrutinib (ACA) metabolism and (ii) to investigate the mechanisms underlying the effects of CYP3A4 variants on the differential kinetic profiles of ACA and ibrutinib.Recombinant human CYP3A4 and variants were expressed using a Bac-to-Bac baculovirus expression system. The cell microsome was prepared and subjected to kinetic study. The analyte concentrations were determined by UPLC-MS/MS. A molecular docking assay was employed to investigate the mechanisms leading to differences in kinetic profiles.The kinetic parameters of ACA, catalyzed by CYP3A4 and 28 of its variants, were determined, including VGenetic polymorphism of CYP3A4 extensively changes its ACA-metabolizing enzymatic activity. In combination with a CYP inhibitor, its inhibitory potency also varied among different variants. Even the same variants exhibited different capabilities catalyzing ACA. Its enzymatic capabilities are probably determined by the distance between the substrate and the heme iron atom, which could be impacted by mutation.
収録刊行物
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- Chemico-Biological Interactions
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Chemico-Biological Interactions 345 109559-, 2021-08-01
Elsevier BV
