Application of mechanism-based CYP inhibition for predicting drug–drug interactions

Abstract

Background: A mechanism-based inhibition of CYPs is characterized by NADPH-, time- and concentration-dependent enzyme inactivation and substrate protection. A significant inactivation of CYPs and particularly the main human hepatic and intestinal CYPs could result in clinical drug–drug interactions (DDIs) and adverse drug reactions. Objective: To address whether DDIs owing to mechanism-based CYP inhibition is predictable based on in vitro inhibitory data. Method: Medline (by means of PubMed up to 26 March 2009) has been searched using proper relevant terms. Result/conclusion: It is possible to predict DDIs caused by mechanism-based CYP inhibition, although the in vitro data do not necessarily translate directly into relative extents of inhibition in vivo because in vivo clinical consequences depend on additional factors that are not easily accounted for in vitro and for reversible inhibition. Incorporation of other important parameters such as CYP degradation rate (k_deg), relative contribution of the CYP inactivated to the victim drug elimination (f_m(CYP)) and inhibition of intestinal CYP-mediated first-pass metabolism of the object drug (F'_gut/F_gut ratio) into the prediction models significantly improves the prediction. Uncertainty of the prediction is mainly from the variability in the estimates of these critical parameters.

Keywords::

• CYP
• drug interaction
• mechanism-based inhibition

Acknowledgments

The authors appreciate the support by the Traditional and Complementary Medicine Research Program, RMIT Health Innovations Research Institute, RMIT University, Bundoora, Victoria 3083, Australia. Zhi-Wei Zhou holds an RMIT University International Postgraduate Scholarship.