Selection of Alternative CYP3A4 Probe Substrates for Clinical Drug Interaction Studies Using In Vitro Data and In Vivo Simulation

@article{Foti2010SelectionOA,
  title={Selection of Alternative CYP3A4 Probe Substrates for Clinical Drug Interaction Studies Using In Vitro Data and In Vivo Simulation},
  author={Robert S. Foti and Dan A. Rock and Larry C. Wienkers and Jan L. Wahlstrom},
  journal={Drug Metabolism and Disposition},
  year={2010},
  volume={38},
  pages={981 - 987}
}
Understanding the potential for cytochrome P450-mediated drug-drug interactions (DDIs) is a critical step in the drug discovery process. DDIs of CYP3A4 are of particular importance because of the number of marketed drugs that are cleared by this enzyme. In response to studies that suggested the presence of several binding regions within the CYP3A4 active site, multiple probe substrates are often used for in vitro CYP3A4 DDI studies, including midazolam (the clinical standard), felodipine… 

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References

SHOWING 1-10 OF 30 REFERENCES

CYP3A4 drug interactions: correlation of 10 in vitro probe substrates.

It is recommended that multiple CYP3A4 probes, representing each substrate group, are used for the in vitro assessment of CYP 3A4-mediated drug interactions.

CYP2C19 Inhibition: The Impact of Substrate Probe Selection on in Vitro Inhibition Profiles

Predictions of in vivo inhibition potency based on the in vitro data suggest that most drug-drug interactions will be identified by either (S)-mephenytoin or omeprazole, although the expected magnitude of the interaction may vary depending on the chosen substrate probe.

CYP2C9 Inhibition: Impact of Probe Selection and Pharmacogenetics on in Vitro Inhibition Profiles

Both genotype and choice of probe substrate must be considered when attempting to predict potential CYP2C9 drug-drug interactions from in vitro data.

Substrate-dependent modulation of CYP3A4 catalytic activity: analysis of 27 test compounds with four fluorometric substrates.

BFC and DBF appear more suitable as an initial screen for CYP3A4 inhibition, whereas the rank order of sensitivity among the fluorometric substrates varied among the individual inhibitors, on average, BFC dealkylation was the most sensitive to inhibition, while BQ dealkYLation was least sensitive.

CYP3A4 Substrate Selection and Substitution in the Prediction of Potential Drug-Drug Interactions

Comparison of simple and multisite mechanistic models and interaction prediction accuracy for each of the in vitro probes indicated that midazolam and quinidine in vitro data provided the best assessment of a potential interaction, with the lowest bias and the highest precision of the prediction.

IMPACT OF PARALLEL PATHWAYS OF DRUG ELIMINATION AND MULTIPLE CYTOCHROME P450 INVOLVEMENT ON DRUG-DRUG INTERACTIONS: CYP2D6 PARADIGM

It is concluded that incorporating parallel pathways provides a valuable step forward in making quantitative predictions of drug-drug interactions from in vitro data.

The Utility of in Vitro Cytochrome P450 Inhibition Data in the Prediction of Drug-Drug Interactions

Findings support the conclusion that P450 in vitro inhibition data are valuable in designing clinical DDI study strategies and can be used to predict the magnitudes of DDI.

Quantitative correlations among CYP3A sensitive substrates and inhibitors: literature analysis.

Quantitative correlations of AUC ratios between four CYP3A inhibitors (fluconazole, erythromycin, verapamil, diltiazem) and ketoconazole were uncovered andSimvastatin and buspirone were consistently more sensitive than midazolam, independent of the inhibitor.

Predicting in vivo drug interactions from in vitro drug discovery data

The principles underlying the generation of in vitro drug metabolism data are described and commonly encountered uncertainties and sources of bias and error that can affect extrapolation of drug–drug interaction information to the clinical setting are highlighted.