Characterization of CYP2D6*1 Inhibition by Rolapitant
MetadataShow full item record
Human cytochrome P450 (CYP) enzymes are hemoproteins, primarily found in the liver, whose role is to metabolize endogenous and exogenous chemicals, including pharmaceuticals. Among these, human CYP2D6 is responsible for approximately 20% of CYP-mediated drug metabolism. The rate and efficacy of this metabolism can be influenced by enzyme inhibition that changes the enzyme’s phenotype and creates risk for altered drug responses and drug-drug interactions in patients. In this study, NK1 receptor antagonist and chemotherapy antiemetic rolapitant was investigated for its long term in vivo inhibition of CYP2D6, shown in clinical trials to inhibit the enzyme for 7 days after one 180 mg dose. Through in vitro assays, rolapitant did not behave as a mechanism-based inactivator or a tight-binding inhibitor as predicted. Instead, rolapitant behaved as a low potency mixed inhibitor. Through the characterization of rolapitant’s inhibitory potency, this study aimed to expand the repertoire of knowledge on P450 inhibitors and their mechanisms in order to ameliorate personalized medicine and drug development, therefore reducing the risk and occurrence of adverse clinical events.