Time-dependent inhibition (TDI) of CYP3A4 and CYP2C9 by noscapine potentially explains 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 IC50 of 10.8 +/- 2.5 mu m and 13.3 +/- 1.2 mu m. Kinetic analysis showed that inhibition of CYP2C9 by noscapine was best fit to a noncompetitive type with K-i value of 8.8 mu m, while inhibition of CYP3A4 by noscapine was best fit to a competitive manner with K-i value of 5.2 mu m. Noscapine also exhibited TDI to CYP3A4 and CYP2C9. The inactivation parameters (K-I and k(inact)) were calculated to be 9.3 mu m and 0.06 min-1 for CYP3A4 and 8.9 mu 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.