ABSTRACT
Over the past decade there has been a substantial improvement in the ability to predict metabolism-based in vivo drug interactions from kinetic data obtained in vitro. This advance has been most evident for interactions that occur at the level of cytochrome P450 (CYP)-catalyzed oxidation and reflects the availability of human tissue samples, cDNA-expressed CYPs, and well-defined substrates and inhibitors of individual enzymes. Irreversible inhibition is an additional mechanism that may reduce the catalytic activity of an enzyme in vitro and in vivo. This mechanism has been extensively characterized in vitro and is particularly common for CYP-mediated biotransformations, in part because of high-energy intermediates that are characteristic of these reactions. Certain CYPs undergo mechanism-based inactivation as a result of conversion of their prosthetic heme groups to products that irreversibly bind to the protein. Many drugs are mechanism-based inhibitors of CYP. This property could affect a drug’s own metabolism or the metabolism of coadministered drugs, which could lead to serious drug interactions.
