Unexpected interaction between CYP3A4 and BI 11634: is BI 11634 interacting with CYP3A4 similar to nifedipine?
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Arti Mathur
Abstract
Background: Interactions between cytochrome P450 3A4 (CYP3A4) and its substrates are complex with multiple binding sites within the active site. BI 11634 is a factor Xa inhibitor in drug development and its interaction with CYP3A4 was evaluated.
Methods: Reaction phenotyping studies were conducted to determine human isoform(s) of cytochrome P450 responsible for BI 11634 metabolism using recombinant CYPs and specific chemical inhibitors. Metabolite identification and quantitation were performed for incubations of [14C]BI 11634 with human liver microsomes (HLMs) or recombinant CYP3A4 (rCYP3A4) using a high-performance liquid chromatography-mass spectrometry-radiomatic detector. Inhibition of the CYP3A4-mediated metabolism of BI 11634 by quinidine was further evaluated.
Results: From the reaction phenotyping studies, it was shown that the metabolism of BI 11634 in HLM was inhibited by ketoconazole and quinidine, well-accepted specific inhibitors of CYP3A4 and CYP2D6, respectively. In contrast, BI 11634 metabolism was exclusively mediated by rCYP3A4. Additional studies confirmed that BI 11634 was metabolized by CYP3A4 to form one major metabolite and this reaction was inhibited by quinidine with a Ki of 7 µM.
Conclusions: These data indicated that BI 11634 may interact with CYP3A4 similar to nifedipine. CYP3A4 substrates have been categorized into three subgroups, including a stand-alone subgroup for dihydropyridine calcium channel blockers such as nifedipine and felodipine. In addition, this study emphasizes the importance of using rCYP in conjunction with approaches relying on inhibition when conducting CYP450 reaction phenotyping studies, as one single method may generate misleading results. The specificity of quinidine as a CYP2D6 inhibitor is questionable as it can also significantly inhibit CYP3A4-mediated metabolism of some compounds.
We thank Dr. Timothy S. Tracy for providing scientific advice. We thank Maxim Chevliakov and Bachir Latli for synthesizing the monohydroxylated BI 11634 (oxidation on the methyl group).
Conflict of interest statement
Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article. Research funding played no role in thestudy design; in the collection, analysis, and interpretationof data; in the writing of the report; or in the decision tosubmit the report for publication.
Research funding: This research was funded in full by Boehringer Ingelheim Pharmaceuticals, Inc.
Employment or leadership: None declared.
Honorarium: None declared.
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©2013 by Walter de Gruyter Berlin Boston
Artikel in diesem Heft
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- Unexpected interaction between CYP3A4 and BI 11634: is BI 11634 interacting with CYP3A4 similar to nifedipine?
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Artikel in diesem Heft
- Masthead
- Masthead
- Editorial
- New challenges for pharmacogenomics
- Reviews in Population Pharmacogenomics
- Cytochrome P450 genetic polymorphisms of Mexican indigenous populations
- Mini Review
- Recent examples on the clinical relevance of the CYP2D6 polymorphism and endogenous functionality of CYP2D6
- Original Articles
- Evaluation of partial area under the concentration time curve to estimate midazolam apparent oral clearance for cytochrome P450 3A phenotyping
- Influence of Allium sativum extract on the hypoglycemic activity of glibenclamide: an approach to possible herb-drug interaction
- A population pharmacokinetic model of remifentanil in pediatric patients using body-weight-dependent allometric exponents
- Unexpected interaction between CYP3A4 and BI 11634: is BI 11634 interacting with CYP3A4 similar to nifedipine?
- Short Communication
- Caffeic acid inhibits organic anion transporters OAT1 and OAT3 in rat kidney
