Contribution of Intestinal Cytochrome P450-Mediated Metabolism to Drug-Drug Inhibition and Induction Interactions

Current drug-drug interaction (DDI) prediction models incorporate intestinal interaction as the ratio of the intestinal availability in the presence and absence of an inhibitor/inducer (FG' and FG, respectively). The incorporation of the gut is commonly associated with a reduced number of false...

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Bibliographic Details
Published in:DRUG METABOLISM AND PHARMACOKINETICS 2010-01, Vol.25 (1), p.28-47
Main Authors: Galetin, Aleksandra, Gertz, Michael, Brian Houston, J.
Format: Article
Language:eng ; jpn
Subjects:
Animals
ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism
CYP3A4
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 Enzyme System - biosynthesis
Drug Evaluation - methods
Drug Interactions
drug-drug interactions
Enzyme Induction - drug effects
Enzyme Inhibitors - pharmacology
Food-Drug Interactions
Humans
induction
inhibition
intestinal first-pass
Intestines - drug effects
Intestines - enzymology
Intestines - metabolism
Models, Statistical
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Summary:Current drug-drug interaction (DDI) prediction models incorporate intestinal interaction as the ratio of the intestinal availability in the presence and absence of an inhibitor/inducer (FG' and FG, respectively). The incorporation of the gut is commonly associated with a reduced number of false negative predictions; however, in some instances a trend for over-prediction is apparent. This differential success is highly dependent on the initial model assumptions and parameter estimates used (often inconsistent between the datasets) and cannot be associated exclusively with the incorporation of the intestine. The current review provides an assessment of the contribution of intestinal inhibition and induction in conjunction with different perpetrator and victim drug-related properties, focusing in particular on victim drugs with high intestinal first-pass extraction (>75%). Recommendations are given in order to avoid significant over-estimation of true positives and increased number of false positive predictions. This review discusses advantages and limitations of different in vitro and in vivo methods for assessing intestinal availability and associated inter-individual variability, due to the sensitivity of the DDI prediction models to the Fg.
ISSN:1347-4367
1880-0920
DOI:10.2133/dmpk.25.28