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Rolapitant is not a mechanism‐based inactivator or tight‐binding inhibitor of CYP2D6 in vitro
Author(s) -
Glass Sarah,
Furge Laura Lowe
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.920.2
Subject(s) - pharmacology , cyp2d6 , chemistry , cyp3a4 , in vivo , drug , metabolite , in vitro , drug metabolism , medicine , biochemistry , metabolism , biology , cytochrome p450 , microbiology and biotechnology
Rolapitant is a NK1 receptor antagonist that was approved by the FDA in September 2015 as a treatment for chemotherapy‐induced nausea and vomiting. In vivo, rolapitant is primarily metabolized by CYP3A4, a member of the P450 superfamily that is responsible for the metabolism of 45% of pharmaceuticals. In clinical studies, it was shown that rolapitant inhibits the activity of another major drug metabolizing P450, CYP2D6, for at least a week after just one dose. Because the inhibition time is long, we hypothesized that rolapitant might be a mechanism‐based inactivator that irreversibly inhibits CYP2D6. Such inactivation could lead to adverse drug‐drug events. Interactions of rolapitant with both CYP3A4 and CYP2D6 were investigated utilizing AutoDock molecular modeling, spectral binding analysis, mass spectrometry metabolite studies, and in vitro inhibition assays. The results were compared with a known mechanism‐based inactivator, SCH 66712, and a tight‐binding inhibitor, quinidine. From this study, it appears that rolapitant is neither a mechanism‐based inactivator nor a tight‐binding inhibitor. Because of this, the in vivo inhibitory potency could be due to the drug's long mean elimination half‐life (7 days). Understanding the mechanism of inhibition by rolapitant has clinical relevance in preventing drug‐drug interactions caused by CYP2D6 inhibition during polypharmacy often occurring during cancer treatment. Support or Funding Information NIH 1R15‐GM086767‐02