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

Abstract

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 IC50 of 10.8 ± 2.5 μm and 13.3 ± 1.2 μm. Kinetic analysis showed that inhibition of CYP2C9 by noscapine was best fit to a noncompetitive type with Ki value of 8.8 μm, while inhibition of CYP3A4 by noscapine was best fit to a competitive manner with Ki value of 5.2 μm. Noscapine also exhibited TDI to CYP3A4 and CYP2C9. The inactivation parameters (KI and kinact) were calculated to be 9.3 μm and 0.06 min-1 for CYP3A4 and 8.9 μm 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 Cmax or 0.5% and 0.4% using unbound Cmax 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 Cmax or 41.8% and 32.7% using unbound Cmax with TDI prediction equation. Conclusions TDI of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine-warfarin interaction. © 2010 The British Pharmacological Society.