Mechanism Based Inactivation of Cytochrome P450 3A4 by 5-Fluoro-2-[4-[(2-phenyl-1H- imidazol-5-yl)methyl]-1-piperazinyl]pyrimidine

Loading...
Thumbnail Image
Authors
Bolles, Amanda K.
Issue Date
2013
Type
Thesis
Language
en_US
Keywords
Research Projects
Organizational Units
Journal Issue
Alternative Title
Abstract
Human cytochrome P450 3A4 (CYP3A4) is responsible for the metabolism of over fifty percent of pharmaceutical drugs on the market today. Inhibition of CYP3A4 can lead to adverse drug-drug interactions. 5-Fluoro-2-[4-[(2-phenyl-1H-imidazol-5-yl)methyl]-1-piperazinyl]pyrimidine (SCH66712) has previously been confirmed as a mechanism based inactivator (MBI) of CYP2D6 and data suggested it could also be an inactivator of CYP3A4 [Palamanda, Casciano, Norton, Clement, Favreau, Lin, Nomeir (2001) Drug Metab Dispos 29, 863-867]. In the current study SCH66712 was shown to be an MBI of CYP3A4. Inactivation of CYP3A4 by SCH66712 was determined to be concentration-, time- and NADPH-dependent. In addition, inactivation of CYP3A4 by SCH66712 was shown to be unaffected by the presence of electrophile scavengers. SCH66712 displays type II binding to CYP3A4, with a spectral binding constant (Ks) of 43 ± 2 μM. For the inactivation of CYP3A4 by SCH66712 the maximal rate constant of inactivation (kinact) was determined to be 0.036 min-1, the inactivator concentration required for half maximum inactivation (KI) was determined to be 2.70 μM, and the efficiency (kinact/KI) of inactivation determined to be 0.013 μM/min. The partition ratio was determined to be 11. suggesting SCH66712 is a potent MBI of CYP3A4. The compilation of these results confirm that SCH66712 is a potent and efficient mechanism based inactivator of CYP3A4.
Description
vi, 37 p.
Citation
Publisher
Kalamazoo College
License
U.S. copyright laws protect this material. Commercial use or distribution of this material is not permitted without prior written permission of the copyright holder. All rights reserved.
Journal
Volume
Issue
PubMed ID
DOI
ISSN
EISSN