Rolapitant Is a Reversible Inhibitor of CYP2D6.

Area of Science:

• Pharmacology
• Drug Metabolism
• Medicinal Chemistry

Background:

• Rolapitant is an NK1 receptor antagonist approved for chemotherapy-induced nausea and vomiting.
• In vivo studies show rolapitant causes moderate, long-lasting CYP2D6 inhibition.
• The mechanism behind rolapitant's prolonged CYP2D6 inhibition requires investigation.

Purpose of the Study:

• To determine if rolapitant is a mechanism-based inactivator of CYP2D6.
• To characterize the interaction between rolapitant and CYP2D6.
• To investigate the discrepancy between in vitro and in vivo CYP2D6 inhibition by rolapitant.

Main Methods:

• In vitro enzyme kinetics assays (NADPH-, time-, concentration-dependent), stopped-flow binding studies, Lineweaver-Burk and Dixon analyses.
• Molecular docking and 1 microsecond molecular dynamics simulations of rolapitant with CYP2D6.
• Drug-drug interaction modeling.

Main Results:

• Rolapitant exhibited type I binding to CYP2D6 (K_s = 1.2 ± 0.4 µM).
• No mechanism-based inactivation or rolapitant metabolites were observed in vitro.
• Rolapitant acted as a mixed, reversible inhibitor (K_i values of 20 and 34 µM).
• Molecular dynamics simulations showed rolapitant binding not consistent with metabolism.

Conclusions:

• Rolapitant is not a mechanism-based inactivator of CYP2D6.
• The reversible inhibition of CYP2D6 by rolapitant does not fully explain the observed in vivo inhibition.
• Further research is needed to elucidate the mechanism of rolapitant's in vivo CYP2D6 interaction.