DRUG-DRUG INTERACTIONS - EFFECT OF QUINIDINE ON NIFEDIPINE BINDING TOHUMAN CYTOCHROME-P450 3A4

Quinidine is a known inhibitor of cytochrome P450-mediated nifedipine metabolism. The interactions of nifedipine and quinidine with human cy tochrome P450 3A4, which metabolizes these drugs, were examined using the kinetics of CO binding to this P450 as a rapid kinetic probe of pr otein 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 pr esent simultaneously, nifedipine interacted with the quinidine-bound P 450 species II, but not species I. These findings indicate that quinid ine acts as an allosteric inhibitor by switching nifedipine binding fr om nifedipine-metabolizing species I to the nonmetabolizing species II .