chapter  11
30 Pages

Mechanism-Based Inhibition of Human Cytochromes P450: In Vitro Kinetics and In Vitro-In Vivo Correlations

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. The most common paradigm in the prediction of in vivo drug interactions has been first to determine the enzyme selectivity of a suspected inhibitor and subsequently to estimate the constant that quantifies the potency of reversible inhibition in vitro. This approach has been successful in identifying clinically important potent competitive inhibitors, such as quinidine, fluoxetine, and itraconazole. However, there is a continuing concern that a number of well-established and clinically important CYP-mediated drug interactions are not predictable from the classical approach that assumes reversible mechanisms of inhibition are ubiquitous.