| 20233183 |
Fang ZZ, Zhang YY, Ge GB, Huo H, Liang SC, Yang L: Time-dependent inhibition (TDI) of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine-warfarin interaction. Br J Clin Pharmacol. 2010 Feb;69(2):193-9.
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 microm and 13.3 +/- 1.2 microm. Kinetic analysis showed that inhibition of CYP2C9 by noscapine was best fit to a noncompetitive type with K (i) value of 8.8 microm, while inhibition of CYP3A4 by noscapine was best fit to a competitive manner with K (i) value of 5.2 microm. Noscapine also exhibited TDI to CYP3A4 and CYP2C9. The inactivation parameters (K (I) and k (inact)) were calculated to be 9.3 microm and 0.06 min (-1) for CYP3A4 and 8.9 microm 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. |
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