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First published on October 12, 2005; DOI: 10.1124/dmd.105.006874

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Received for publication August 16, 2005.
Revised October 7, 2005.
Accepted for publication October 7, 2005.

Prediction of Time-Dependent CYP3A4 Drug-Drug Interactions - Impact of Enzyme Degradation, Parallel Elimination Pathways and Intestinal Inhibition

Aleksandra Galetin 1*, Howard Burt 1, Laura Gibbons 1, J. Brian Houston 1

1 School of Pharmacy, University of Manchester

* Address correspondence to: E-mail: aleksandra.galetin{at}manchester.ac.uk

Abstract

Time-dependent inhibition of CYP3A4 often results in clinically significant drug-drug interactions. In the current study, 37 in vivo cases of irreversible inhibition were collated, focusing on macrolides (erythromycin, clarithromycin and azithromycin) and diltiazem as inhibitors. The interactions included 17 different CYP3A substrates showing up to 7-fold increase in AUC (13.5 % of studies were in the range of potent inhibition). A systematic analysis of the impact of CYP3A4 degradation half-life (mean t1/2deg=3 days, ranging from 1-6 days) on the prediction of the extent of interaction for compounds with a differential contribution from CYP3A4 to the overall elimination (defined by fmCYP3A4) was performed. Although the prediction accuracy was very sensitive to CYP3A4 degradation rate for substrates mainly eliminated by this enzyme (fmCYP3A4 ≥ 0.9), minimal effects are observed when CYP3A4 contributes less than 50% to the overall elimination in cases when the parallel elimination pathway is not subject to inhibition. Use of the mean CYP3A4 t1/2deg (3 days), average unbound systemic plasma concentration of the inhibitor and the corresponding fmCYP3A4 resulted in 89% studies predicted within 2-fold of the in vivo value. The impact of the interaction in the gut wall was assessed by assuming maximal intestinal inhibition of CYP3A4. Although a reduced number of false negative predictions was observed there was an increased number of over-predictions, and generally a loss of prediction accuracy was observed. The impact of the possible interplay between CYP3A4 and efflux transporters on the intestinal interaction requires further evaluation.


Key words: CYP3A, drug-drug interactions, in vitro-in vivo prediction, mechanism-based inhibition


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