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

Zhi Wei Zhou, Shu Feng Zhou

Research output: Contribution to journalReview articlepeer-review

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 (kdeg), relative contribution of the CYP inactivated to the victim drug elimination (fm(CYP)) and inhibition of intestinal CYP-mediated first-pass metabolism of the object drug (F′gut/Fgut 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.

Original languageEnglish (US)
Pages (from-to)579-605
Number of pages27
JournalExpert Opinion on Drug Metabolism and Toxicology
Volume5
Issue number6
DOIs
StatePublished - Jun 2009
Externally publishedYes

Keywords

  • CYP
  • Drug interaction
  • Mechanism-based inhibition

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Fingerprint

Dive into the research topics of 'Application of mechanism-based CYP inhibition for predicting drug-drug interactions'. Together they form a unique fingerprint.

Cite this