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Drug-drug interactions: Effect of quinidine on nifedipine binding to human cytochrome P450 3A4

Authors
  • Koley, Aditya P.
  • Robinson, Richard C.
  • Markowitz, Allen
  • Friedman, Fred K.
Type
Published Article
Journal
Biochemical Pharmacology
Publisher
Elsevier
Publication Date
Jan 01, 1997
Accepted Date
Dec 06, 1996
Volume
53
Issue
4
Pages
455–460
Identifiers
DOI: 10.1016/S0006-2952(96)00836-2
Source
Elsevier
Keywords
License
Unknown

Abstract

Quinidine is a known inhibitor of cytochrome P450-mediated nifedipine metabolism. The interactions of nifedipine and quinidine with human cytochrome P450 3A4, which metabolizes these drugs, were examined using the kinetics of CO binding to this P450 as a rapid kinetic probe of protein conformation and dynamics. This approach showed that nifedipine and quinidine bind to different P450 3A4 species, respectively termed species I and II, with distinct conformations. When both drugs were present simultaneously, nifedipine interacted with the quinidine-bound P450 species II, but not species I. These findings indicate that quinidine acts as an allosteric inhibitor by switching nifedipine binding from nifedipine-metabolizing species I to the nonmetabolizing species II.

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