Time-dependent inhibition (TDI) of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine–warfarin interaction

摘要

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT ? Clinical cases reported to the Swedish adverse drug interactions register (SWEDIS) indicated that drug–drug interaction (DDI) existed when warfarin was co-administered with noscapine. ? In vitro testing with recombinant human enzyme showed that noscapine inhibited CYP3A4 and CYP2C9 with an IC ₅₀ of around 1 μ m . ? However, the clinical relevance of these in vitro data remains to be explored. WHAT THIS STUDY ADDS ? Noscapine was demonstrated to be both a reversible inhibitor and a time-dependent inhibitor to CYP3A4 and CYP2C9. ? DDI magnitude predicted from reversible inhibition and time-dependent inhibition (TDI) kinetic parameters showed that the TDI might be a noteworthy factor resulting in clinical noscapine–warfarin interaction. AIMS To investigate the inhibition potential and kinetic information of noscapine to seven CYP isoforms and extrapolate in vivo noscapine-warfarin interaction magnitude from in vitro data. METHODS The activities of seven CYP isoforms (CYP3A4, CYP1A2, CYP2A6, CYP2E1, CYP2D6, CYP2C9, CYP2C8) in human liver microsomes were investigated following co- or preincubation with noscapine. A two-step incubation method was used to examine in vitro time-dependent inhibition (TDI) of noscapine. Reversible and TDI prediction equations were employed to extrapolate in vivo noscapine–warfarin interaction magnitude from in vitro data. RESULTS Among seven CYP isoforms tested, the activities of CYP3A4 and CYP2C9 were strongly inhibited with an IC ₅₀ of 10.8 ± 2.5 μ m and 13.3 ± 1.2 μ m . Kinetic analysis showed that inhibition of CYP2C9 by noscapine was best fit to a noncompetitive type with K _i value of 8.8 μ m , while inhibition of CYP3A4 by noscapine was best fit to a competitive manner with K _i value of 5.2 μ m . Noscapine also exhibited TDI to CYP3A4 and CYP2C9. The inactivation parameters ( K _I and k _inact ) were calculated to be 9.3 μ m and 0.06 min ^?1 for CYP3A4 and 8.9 μ m and 0.014 min ^?1 for CYP2C9, respectively. The AUC of (S)-warfarin and (R)-warfarin was predicted to increase 1.5% and 1.1% using C _max or 0.5% and 0.4% using unbound C _max with reversible inhibition prediction equation, while the AUC of (S)-warfarin and (R)-warfarin was estimated to increase by 110.9% and 48.9% using C _max or 41.8% and 32.7% using unbound C _max with TDI prediction equation. CONCLUSIONS TDI of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine–warfarin interaction.